CN102812008B - Therapeutic agent or preventive agent for urine collection disorder - Google Patents
Therapeutic agent or preventive agent for urine collection disorder Download PDFInfo
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- CN102812008B CN102812008B CN201180016947.6A CN201180016947A CN102812008B CN 102812008 B CN102812008 B CN 102812008B CN 201180016947 A CN201180016947 A CN 201180016947A CN 102812008 B CN102812008 B CN 102812008B
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- compound
- mmol
- reaction
- phenyl
- ethyl acetate
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- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 57
- 230000003449 preventive effect Effects 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 210000002700 urine Anatomy 0.000 title abstract description 15
- 229940124597 therapeutic agent Drugs 0.000 title abstract 3
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- -1 methoxyl group Chemical group 0.000 claims description 76
- 206010046555 Urinary retention Diseases 0.000 claims description 41
- 230000027939 micturition Effects 0.000 claims description 35
- 125000004432 carbon atom Chemical group C* 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 230000001225 therapeutic effect Effects 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 206010046543 Urinary incontinence Diseases 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
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- 206010027566 Micturition urgency Diseases 0.000 claims description 9
- 241001597008 Nomeidae Species 0.000 claims description 8
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- 239000000470 constituent Substances 0.000 claims description 4
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Disclosed is a therapeutic agent or a preventive agent efficacious in treating urine collection disorder, which shows improved side effects based on an anticholinergic effect and also shows an analgesic effect. Specifically disclosed is a therapeutic agent or a preventive agent for urine collection disorder which comprises, as the active ingredient, a cyclohexane derivative, a typical example of which is represented by formula (3), a pharmacologically acceptable salt thereof or a prodrug of the same.
Description
Technical field
The present invention relates to therapeutical agent or the preventive of retention of urine obstacle.
Background technology
When retention of urine obstacle is retention of urine, urine cannot store the state of enough amounts in bladder, and cardinal symptom has: frequent micturition, the urinary incontinence and urgency.Frequent micturition refers to the state exceeding normal voiding number of times, and the urinary incontinence refers to that urine independently or does not unconsciously spill, and is the state causing health, social concern, and urgency refers to state that is that occur suddenly, strong, that present hard to bear strong urine meaning.At present, the therapeutical agent for retention of urine obstacles such as frequent micturition, the urinary incontinence or urgencies mainly uses anticholinergic drug.Anticholinergic drug is combined with M-ChR, plays the medicament of receptor antagonism (cholinolytic effect).
The patient presenting the retention of urine obstacles such as frequent micturition, the urinary incontinence or urgency sometimes main suit with pain, such as, when being caused by interstitial cystitis, known while the retention of urine obstacles such as frequent micturition, the urinary incontinence or urgency, also with retention of urine phase abdomen pain or the pain in vesicourethral portion or unplessantness displeasure when urinating.
At present as in the medicine of analgesics utilization, there is example frequent micturition or this kind of retention of urine obstacle of the urinary incontinence being shown to validity.Such as report: non-steroidal anti-inflammatory analgesic loxoprofen can improve nocturnal pollakiuria (non-patent literature 1), reports in addition: the non-narcotic analgesics U-26225A of opium system is for frequent micturition or the urinary incontinence effective (patent documentation 1).
On the other hand; report; pyrazole derivatives (patent documentation 2) or with the aromatic ring of pyrazole ring bonding on there is the following formula of alkylsulfonyl cyclohexane derivant (patent documentation 3) be the compound with analgesic effect, but do not have the report to retention of urine obstacle display effect.
[changing 1]
Patent documentation
Patent documentation 1: No. 98/046216th, International Publication
Patent documentation 2: No. 08/105383rd, International Publication
Patent documentation 3: No. 00/066562nd, International Publication
Non-patent literature
The people such as non-patent literature 1:Saito M, Int J Urol., the 12nd volume, 779 pages in 2005.
Summary of the invention
But, the anticholinergic drug that the retention of urine obstacles such as frequent micturition, the urinary incontinence or urgency use is based on its pharmacological action, have the gastrointestinal symptoms such as thirsty, constipation, the side effects such as recycle system symptom and the paruria such as renal shutdown, residual urine such as orthostatic hypotension, its use is restricted.In addition, loxoprofen has the side effect of Digestive tract, and U-26225A has the side effect of Nausea and vomiting, the distinctive Digestive tract of opium system medicine such as dizzy or dizzy and central nervous system, and for the use of these medicines, its use is restricted.
Therefore, the object of the present invention is to provide the side effect based on cholinolytic effect to improve and there is analgesic activity, to the effective therapeutical agent of the treatment of retention of urine obstacle or preventive simultaneously.
The present inventor has carried out in depth studying for solving above-mentioned problem, found that: the novel cyclohexane derivatives of the analgesic effect that display is excellent has excellent treatment or preventive effect for retention of urine obstacle, and extremely low based on the side effect of cholinolytic effect, thus complete the present invention.
That is, the invention provides therapeutical agent or the preventive of retention of urine obstacle, it contains the cyclohexane derivant shown in general formula (I), the acceptable salt of its pharmacology or its prodrug as effective constituent:
[changing 2]
[in formula, A is the substituting group shown in general formula (IIa) or (IIb),
[changing 3]
R
1and R
2respective independence is the alkoxyl group of the haloalkyl of hydrogen atom, chlorine atom, carbonatoms 1-3, the alkyl of carbonatoms 1-4 or carbonatoms 1-4, R
3for hydrogen atom or chlorine atom, R
4for fluorine atom, hydroxymethyl or hydroxyl, R
5and R
6respective independence be the alkyl-carbonyl oxygen base of the alkoxyl group of the haloalkyl of hydrogen atom, fluorine atom, carbonatoms 1-3, carboxyl, methoxycarbonyl, ethoxy carbonyl, carbonatoms 1-4, hydroxyl or carbonatoms 2-5, or it can form oxo base, R together
7and R
8respective independence, be hydrogen atom or fluorine atom, Y is Sauerstoffatom or sulphur atom, and Z is nitrogen-atoms or methyne].
In above-mentioned cyclohexane derivant, preferred R
1and R
2respective independence is trifluoromethyl, methyl or methoxy; More preferably R
3for hydrogen atom, R
4for hydroxymethyl or hydroxyl, R
5and R
6respective independence is hydrogen atom, fluorine atom, trifluoromethyl, carboxyl, methoxyl group, hydroxyl or ethanoyl oxygen base (can form oxo base together).
The therapeutical agent of more preferably above-mentioned retention of urine obstacle or preventive are therapeutical agent or the preventive of frequent micturition, the urinary incontinence or urgency.
Invention effect
In the therapeutical agent of retention of urine obstacle of the present invention or preventive, the side effect based on cholinolytic effect is low, therefore can guarantee security, has significant result for the treatment of to retention of urine obstacle simultaneously.And have analgesic effect concurrently, therefore, when retention of urine obstacle is with pain, its result for the treatment of also Worth Expecting.
Accompanying drawing explanation
Fig. 1 represents figure cyclohexane derivant intravenous administration of the present invention being brought out the effect of frequent micturition rat model for endoxan monohydrate (hereinafter referred to as endoxan).
Embodiment
The therapeutical agent of retention of urine obstacle of the present invention or the feature of preventive are: it contains the cyclohexane derivant shown in general formula (I), the acceptable salt of its pharmacology or its prodrug as effective constituent:
[changing 4]
[in formula, A is the substituting group shown in following general formula (IIa) or (IIb),
[changing 5]
R
1and R
2respective independence is the alkoxyl group of the haloalkyl of hydrogen atom, chlorine atom, carbonatoms 1-3, the alkyl of carbonatoms 1-4 or carbonatoms 1-4, R
3for hydrogen atom or chlorine atom, R
4for fluorine atom, hydroxymethyl or hydroxyl, R
5and R
6respective independence be the alkyl-carbonyl oxygen base of the alkoxyl group of the haloalkyl of hydrogen atom, fluorine atom, carbonatoms 1-3, carboxyl, methoxycarbonyl, ethoxy carbonyl, carbonatoms 1-4, hydroxyl or carbonatoms 2-5, or it can form oxo base, R together
7and R
8respective independence, be hydrogen atom or fluorine atom, Y is Sauerstoffatom or sulphur atom, and Z is nitrogen-atoms or methyne].
" alkyl of carbonatoms 1-4 " represents the alkyl of the straight-chain of carbonatoms 1-4, branched, ring-type, such as, can enumerate: methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, Cvclopropvlmethvl, normal-butyl, sec-butyl or the tertiary butyl.
" alkoxyl group of carbonatoms 1-4 " represents the alkyl-oxygen base of carbonatoms 1-4 straight-chain, branched, ring-type, such as, can enumerate: methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, cyclopropyl oxygen base, n-butoxy, sec-butoxy or tert.-butoxy.
" haloalkyl of carbonatoms 1-3 " represents part or all group replaced by halogen atom (halogen atom represents fluorine atom, hydrogen atom, bromine atoms or atomic iodine) of the hydrogen atom on the straight-chain alkyl of carbonatoms 1-3, such as, can enumerate: chloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl, trichloromethyl or pentafluoroethyl group.
" the alkyl-carbonyl oxygen base of carbonatoms 2-5 " such as can be enumerated: ethanoyl oxygen base, acetoxyl group, propionyloxy, isopropenoxy, butyryl acyloxy or isobutyl acyloxy or new pentane acyloxy.
In general formula (I), A is preferably general formula (IIa), and Y is preferably Sauerstoffatom, and Z is preferably methyne.
R
1be preferably hydrogen atom, chlorine atom, trifluoromethyl, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, be more preferably trifluoromethyl, methyl, methoxyl group, more preferably methyl.
R
2be preferably hydrogen atom, chlorine atom, trifluoromethyl, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, be more preferably methoxyl group.
R
3be preferably hydrogen atom, R
4be preferably hydroxymethyl, hydroxyl, be more preferably hydroxyl.
R
5be preferably hydrogen atom, fluorine atom, trifluoromethyl, carboxyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, hydroxyl, ethanoyl oxygen base, propionyloxy, butyryl acyloxy or isobutyl acyloxy; be more preferably hydrogen atom, hydroxyl, carboxyl, more preferably hydroxyl.
R
6be preferably hydrogen atom, fluorine atom, trifluoromethyl, carboxyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, hydroxyl, ethanoyl oxygen base, propionyloxy, butyryl acyloxy or isobutyl acyloxy; be more preferably hydrogen atom, hydroxyl, more preferably hydrogen atom.R
5and R
6oxo base can be formed together.
R
7and R
8be preferably hydrogen atom.
In compound shown in general formula (I) or the acceptable salt of its pharmacology (hereinafter referred to as compound (I)), preferred concrete example is as shown in table 1, but they do not limit the present invention.
[table 1-1]
[table 1-2]
[table 1-3]
[table 1-4]
Should illustrate, when there is asymmetric carbon in compound (I), all enantiomers and their mixture comprise in the present invention.
Further, when there is steric isomer in compound (I), all steric isomers and their mixture comprise in the present invention.
" the acceptable salt of pharmacology " such as can be enumerated: hydrochloride, vitriol, phosphoric acid salt, the inorganic acid salts such as hydrobromate, oxalate, malonate, Citrate trianion, fumarate, lactic acid salt, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbate salt, mesylate, tosilate, the organic acid salts such as cinnamate, sodium salt, sylvite, calcium salt, magnesium salts, the inorganic base salts of ammonium salt etc., and methyl amine salt, diethylamine salt, front three amine salt, triethylamine salt, pyridinium salt, triethanolamine salt, ethylenediamine salt, organic alkali salt such as guanidinesalt.Further, compound (I) can form hydrate, solvate, and polymorphic is also contained in wherein.
Compound (I) such as can synthesize according to following manufacture method.If no special instructions, the symbol in each reaction formula is identical with implication defined above.
When starting compound has carboxyl or hydroxyl, the conventional blocking group used can be introduced, after reaction, blocking group can be removed as required.The blocking group of hydroxyl such as can be enumerated: the alkyl of carbonatoms 1-4, phenyl, trityl, the aralkyl (such as benzyl) of carbonatoms 1-4, acyl group (such as formyl radical, acetyl or benzoyl base), the aralkyl-carbonyl (such as benzyloxycarbonyl group) of carbonatoms 7-10, replacement silyl (such as trimethyl silyl, triethylsilyl or t-butyldimethylsilyl).The blocking group of carboxyl such as can enumerate the alkyl of carbonatoms 1-4.
The removing of above-mentioned blocking group is different according to the kind of blocking group, can carry out according to the method for known document (PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (WILEY-INTERSCIENCE)) or the method based on it.
In following manufacture method, starting compound can use salt.Salt can enumerate the salt same with the acceptable salt of above-mentioned pharmacology.
The compound (I) obtained by following manufacture method can according to known method separation and purification, and known method such as can be enumerated: solvent extraction, recrystallization, chromatogram.
When compound (I) is containing optical isomer, steric isomer, positional isomers, rotational isomer, according to known synthetic method and separation method, Isomers can be obtained respectively in the form of a single compound.
(manufacture method 1: the manufacture method of compound (Ic), compound (Id), compound (Ie) and compound (If))
[changing 6]
[in formula, R
5aand R
6arespective independence is the haloalkyl, carboxyl etc. of hydrogen atom, carbonatoms 1-3, R
7and R
8respective independence, be the alkyl etc. of carbonatoms 1-4, other each symbol is identical with implication defined above].
Compound (Ic) obtains by making compound (Ia) alkylation, and compound (Id) obtains by making compound (Ib) alkylation.Compound (Ie) obtains by making compound (Ia) acylations, and compound (If) obtains by making compound (Ib) acylations.
(step 1 and step 2)
The alkylated reaction of compound (Ia) or compound (Ib) normally makes compound (Ia) or compound (Ib) react to carry out with halogenated alkyl in solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, acetone, acetonitrile or DMF, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: the hydrogen-carbonate such as sodium bicarbonate, saleratus basic metal class, the alkali metal carbonate such as salt of wormwood, cesium carbonate class, amine, potassium tert.-butoxide or the sodium hydrides such as triethylamine, diisopropylethylamine, pyridine.
Relative to 1 mole compound (Ia) or compound (Ib), the preferred 0.5-6 mole of usage quantity of above-mentioned alkali, more preferably 0.8-3 mole.
Relative to 1 mole compound (Ia) or compound (Ib), the preferred 0.5-5 mole of usage quantity of above-mentioned halogenated alkyl, more preferably 0.8-2 mole.
The temperature of reaction of abovementioned alkylization reaction preferably-78 to 200 DEG C, more preferably-20 to 100 DEG C.
The reaction times of abovementioned alkylization reaction is different according to reaction conditions, preferably 5 minutes-78 hours, more preferably 30 minutes-48 hours.
(step 3 and step 4)
The acylation reaction of compound (Ia) or compound (Ib) normally makes compound (Ia) or compound (Ib) react to carry out with the acylation agent such as etheride or acid anhydrides in solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the halons such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, the ethers such as tetrahydrofuran (THF), 1,2-glycol dimethyl ether, Isosorbide-5-Nitrae-diox, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: pyridine, triethylamine, diisopropylethylamine or N, N-dimethyl aminopyridine etc.
Relative to 1 mole compound (Ia) or compound (Ib), the preferred 0.5-3 mole of usage quantity of above-mentioned etheride or acid anhydrides, more preferably 0.8-1.5 mole.
Relative to 1 mole compound (Ia) or compound (Ib), the preferred 0.1-6 mole of usage quantity of above-mentioned alkali, more preferably 0.8-3 mole.
The temperature of reaction of above-mentioned acylation reaction preferably-20 to 150 DEG C, more preferably 0-100 DEG C.
The reaction times of above-mentioned acylation reaction is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(manufacture method 2: the manufacture method of compound (Ih))
[changing 7]
[in formula, R
5band R
6brespective independence, be haloalkyl, the alkoxyl group of carbonatoms 1-4, the alkyl-carbonyl oxygen base etc. of carbonatoms 2-5 of hydrogen atom, fluorine atom, carbonatoms 1-3, other each symbol is identical with implication defined above].
Compound (Ih) fluoridizes acquisition by making compound (Ig).
(step 5)
The fluoridation of compound (Ig) normally makes compound (Ig) and fluorizating agent react to carry out in a solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, methylene dichloride, chloroform, tetracol phenixin, 1, the halons such as 2-ethylene dichloride, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1, the alkyl such as ethers or the acetonitrile nitriles such as 4-diox, also can use their mixed solvent.
Above-mentioned fluorizating agent such as can be enumerated: the alkylamino sulfur trifluorides such as (dimethylamino) sulfur trifluoride (DAST), two (2-methoxy ethyl) amino borontrifluoride sulfuric acid.
Relative to 1 mole compound (Ig), the preferred 0.25-20 mole of usage quantity of above-mentioned fluorizating agent, more preferably 0.5-4 mole.
The temperature of reaction of above-mentioned fluoridation preferably-20 to 150 DEG C, more preferably 0-100 DEG C.
The reaction times of above-mentioned fluoridation is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(manufacture method 3: the manufacture method of compound (Ij))
[changing 8]
[in formula, each symbol is identical with implication defined above].
Compound (Ij) fluoridizes acquisition by making compound (Ii).
(step 6)
The fluoridation of compound (Ii) normally makes compound (Ii) and fluorizating agent react to carry out in a solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, methylene dichloride, chloroform, tetracol phenixin, 1, the halons such as 2-ethylene dichloride, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1, the ethers such as 4-diox, or the alkyl nitrile such as acetonitrile, or also can use their mixed solvent.
Above-mentioned fluorizating agent such as can be enumerated: the alkylamino sulfur trifluorides such as (dimethylamino) sulfur trifluoride (DAST), two (2-methoxy ethyl) amino borontrifluoride sulfuric acid.
Relative to 1 mole compound (Ii), the preferred 0.25-20 mole of usage quantity of above-mentioned fluorizating agent, more preferably 0.5-4 mole.
The temperature of reaction of above-mentioned fluoridation preferably-20 to 150 DEG C, more preferably 0-100 DEG C.
The reaction times of above-mentioned fluoridation is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(manufacture method 4: the manufacture method of compound (Ik) and compound (Il))
[changing 9]
[in formula, each symbol is identical with implication defined above].
Compound (Ik) and compound (Il) are by obtaining compound (Ii) reduction.
(step 7)
The reduction reaction of compound (Ii) normally in a solvent, makes compound (Ii) and reductive agent react to carry out, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, diethyl ether, the alcohols such as methyl alcohol, ethanol, Virahol, also can use their mixed solvent.
Above-mentioned reductive agent such as can be enumerated: sodium borohydride, lithium borohydride, diisobutyl aluminium hydride, lithium aluminum hydride, triethyl lithium hydride, two (2-methoxy ethoxy) sodium aluminum hydride or borane complex.
Relative to 1 mole compound (Ii), the preferred 0.25-100 mole of usage quantity of above-mentioned reductive agent, more preferably 0.5-20 mole.
The temperature of reaction of above-mentioned reduction reaction preferably-78 to 150 DEG C, more preferably-78 to 100 DEG C.
Reaction times of above-mentioned reduction reaction is different from reaction conditionss such as the amounts of temperature of reaction or reductive agent, preferably 5 minutes-72 hours, more preferably 30 minutes-24 hours.
(manufacture method 5: the manufacture method of compound (Im) and compound (In))
[changing 10]
[in formula, each symbol is identical with implication defined above].
Compound (Im) and compound (In) obtain by making compound (Ii) trifluoromethylation.
(step 8)
Trifluoromethyl agent such as can enumerate the silicoorganic compound such as (trifluoromethyl) trimethyl silane.Use the reaction of the trifluoromethylation of silicoorganic compound can carry out according to the method for known document (Journal of the American Chemical Society, 39 volumes, 393-395 page in 1989) or the method based on it.
(manufacture method 6: the manufacture method of compound (Io))
[changing 11]
[in formula, each symbol is identical with implication defined above].
Compound (SI) makes Witting reagent (LI) and compound (Ii) act on, then be hydrolyzed acquisition.Witting reagent (LI) can utilize commercially available compound, also can synthesize according to method known in those skilled in the art.Compound (Io) obtains by making compound (SI) be oxidized.
(step 9)
The Witting reaction of compound (Ii) normally makes compound (Ii) and Witting reagent react carry out in solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, ethylene glycol dimethyl ether, diethyl ether, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: diisopropyl amido lithium, the potassium trimethyl carbinol, sodium hydride, phenyl lithium or tert-butyl lithium.
Relative to 1 mole compound (Ii), the preferred 0.5-3 mole of usage quantity of above-mentioned alkali, more preferably 0.8-2 mole.
Relative to 1 mole compound (Ii), the preferred 0.5-3 mole of usage quantity of compound (LI), more preferably 0.8-2 mole.
The temperature of reaction of above-mentioned Witting reaction preferably-78 to 100 DEG C, more preferably-78 to 50 DEG C.
The reaction times of above-mentioned Witting reaction is different according to the reaction conditions of temperature of reaction etc., preferably 5 minutes-48 hours, more preferably 30 minutes-24 hours.
The hydrolysis reaction carried out to obtain compound (SI) carries out suitable not hindering in the solvent of reaction of selection.Do not hinder the solvent of reaction such as can enumerate: the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, the alcohols such as methyl alcohol, ethanol, the trimethyl carbinol, acetonitrile or water, also can use their mixed solvent.
The preferred 0.1-12M of concentration of the acid used in said hydrolyzed reaction, relative to 1 mole compound (Ii), its usage quantity preferably 1 mole-excessive.
The acid used in said hydrolyzed reaction such as can be enumerated: the organic acids such as the mineral acid such as hydrochloric acid, sulfuric acid or acetic acid.
The temperature of reaction of said hydrolyzed reaction preferably-20 to 200 DEG C, more preferably 0-100 DEG C.
The reaction times of said hydrolyzed reaction is different according to reaction conditions, preferably 5 minutes-48 hours, more preferably 30 minutes-24 hours.
(step 10)
The oxygenant used in the oxidizing reaction of compound (SI) such as can be enumerated: chromic oxide (VI)-acetic acid, Jones reagent or clorox etc.Above-mentioned oxidizing reaction can be carried out according to method known in those skilled in the art.
(manufacture method 7: the manufacture method of compound (Ii))
[changing 12]
[in formula, R
9and R
10respective independence is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl etc., or R
9, R
10ethylidene (-CH can be formed together
2cH
2-) or propylidene (-CH
2cH
2cH
2-) etc., other each symbol is identical with implication defined above].
Compound (Ii) is by obtaining compound (Ip) deprotection.
(step 11)
The deprotection reaction of compound (Ip) can carry out according to the method for known document (PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (WILEY-INTERSCIENCE)) or the method based on it.
(manufacture method 8: the manufacture method of compound (IIIb))
[changing 13]
[in formula, each symbol is identical with implication defined above].
Compound (IIIb) obtains by making compound (IIIa) chlorination.
(step 12)
The chlorination reaction of compound (IIIa) normally makes compound (IIIa) and chlorination reaction carry out in a solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the halons such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, acetonitrile or ethyl acetate, also can use their mixed solvent.
Above-mentioned chlorizating agent such as can be enumerated: N-chlorosuccinimide (NCS).
Relative to 1 mole compound (IIIa), the preferred 0.5-2 mole of usage quantity of above-mentioned chlorizating agent, more preferably 0.8-1.2 mole.
The preferred 0-200 DEG C of temperature of reaction of above-mentioned chlorination reaction, more preferably 0-120 DEG C.
The reaction times of above-mentioned chlorination reaction is different according to the reaction conditions of temperature of reaction etc., preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
The manufacture method of manufacture method 9:(compound (IIIa))
[changing 14]
[in formula, each symbol is identical with implication defined above].
Compound (IIIa) is obtained by the cyclisation of compound (LII) with compound (SII).Compound (LII) can utilize commercially available compound, also can synthesize according to method known in those skilled in the art.
(step 13)
The cyclization of compound (LII) and compound (SII) normally carries out not hindering in the solvent of reaction of suitably selecting.Do not hinder the solvent of reaction such as can enumerate: the alcohols such as methyl alcohol, ethanol, Virahol, methylene dichloride, chloroform, tetracol phenixin, 1, the halons such as 2-ethylene dichloride, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1, the ethers such as 4-diox, benzene, toluene, acetic acid or water, also can use their mixed solvent.
Relative to 1 mole compound (SII), the preferred 0.5-1.5 mole of usage quantity of compound (LII), more preferably 0.8-1.2 mole.
Should illustrate, above-mentioned cyclization can use catalyzer, and above-mentioned catalyzer such as can be enumerated: the organic bases such as triethylamine, pyridine, the organic acids such as the mineral acid such as hydrochloric acid, sulfuric acid or acetic acid.
Relative to 1 mole compound (SII), the preferred 0.1-3 mole of usage quantity of above-mentioned catalyzer.
The preferred 0-200 DEG C of temperature of reaction of above-mentioned cyclization, more preferably 0-120 DEG C.
The reaction times of above-mentioned cyclization is different according to the reaction conditions of temperature of reaction etc., preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(manufacture method 10: the manufacture method of compound (IV))
[changing 15]
[in formula, each symbol is identical with implication defined above].
Compound (IV) is obtained with oxidation by the deprotonation of compound (SIII).Above-mentioned oxidizing reaction can be carried out according to the method for known document (Tetrahedron, 45 volumes, 5703-5742 page in 1989) or the method based on it.
(step 14)
The deprotonation reaction of compound (SIII) and oxidizing reaction normally make compound (SIII) carry out with alkali and oxidant reaction in dehydrated solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, heptane, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, diethyl ether, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: the butyllithiums such as n-Butyl Lithium, s-butyl lithium, tert-butyl lithium.
Relative to 1 mole compound (SIII), the preferred 0.8-5 mole of usage quantity of above-mentioned alkali, more preferably 0.9-3 mole.
Relative to 1 mole compound (SIII), the preferred 0.8-5 mole of usage quantity of compound (LIII), more preferably 0.9-3 mole.
The oxygenant used in above-mentioned oxidizing reaction such as can be enumerated: 3-phenyl-2-(phenyl sulfonyl)-1,2-oxaziridine (oxaziridine).
The temperature of reaction of above-mentioned deprotonation reaction and oxidizing reaction preferably-78 to 150 DEG C, more preferably 0-50 DEG C.
The reaction times of above-mentioned deprotonation reaction and oxidizing reaction is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(manufacture method 11: the manufacture method of midbody compound (VI))
[changing 16]
[in formula, each symbol is identical with implication defined above].
Compound (VI) is that compound (LIV) and compound (LV) are reacted, then by gained compound (V) solvolysis is obtained.Compound (LIV) and compound (LV) can utilize commercially available compound, also can synthesize according to method known in those skilled in the art.
(step 15)
The reaction of compound (LIV) and compound (LV) is normally carried out in dehydrated solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, diethyl ether, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: the lithium alkylide such as lithium methide, n-Butyl Lithium class, the salt of the dialkyl amines such as lithium diisopropyl amido, two (trimethyl silyl) amido lithium, two (trimethyl silyl) amido potassium.
Relative to 1 mole compound (LIV), the preferred 0.8-5 mole of usage quantity of above-mentioned alkali, more preferably 0.9-3 mole.
Relative to 1 mole compound (LIV), the preferred 0.8-5 mole of usage quantity of compound (LV), more preferably 0.9-3 mole.
The temperature of reaction of above-claimed cpd (LIV) and compound (LV) preferably-78 to 150 DEG C, more preferably-78 to 100 DEG C.
Above-claimed cpd (LIV) is different according to reaction conditions from the reaction times of compound (LV), preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(step 16)
Above-mentioned solvolysis reaction normally carries out in solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the alcohols such as methyl alcohol, ethanol or water, can use their mixed solvent yet.
Above-mentioned alkali such as can be enumerated: salt of wormwood, sodium carbonate, potassium hydroxide or sodium hydroxide.
Relative to 1 mole compound (V), the preferred 0.5-10 mole of usage quantity of above-mentioned alkali, more preferably 0.8-3 mole.
The temperature of reaction of above-mentioned solvolysis reaction preferably-20 to 150 DEG C, more preferably 0-100 DEG C.
The reaction times of above-mentioned solvolysis reaction is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(manufacture method 12: the manufacture method of midbody compound (SIIa))
[changing 17]
[in formula, R
11for the alkoxyl group etc. of hydrogen atom, imidazolyl, N-methoxy-. N-methyl amino or methoxy or ethoxy etc., other each symbol is identical with implication defined above].
Compound (SIIa) is that compound (VI) and compound (LVI) are reacted, then by gained compound (VII) oxidation is obtained.Compound (SIIa) also obtains by making compound (VI) and compound (LVII) react.Compound (LVI) and compound (LVII) can utilize commercially available compound, also can synthesize according to method known in those skilled in the art.
(step 17 or step 18)
The reaction of compound (VI) and compound (LVI) or compound (LVII) is normally carried out in dehydrated solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, diethyl ether, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: the salt of the dialkyl amine such as the lithium alkylide such as lithium methide, n-Butyl Lithium class, lithium diisopropyl amido, two (trimethyl silyl) amido lithium, two (trimethyl silyl) amido potassium.
Relative to 1 mole compound (VI), the preferred 0.8-5 mole of usage quantity of above-mentioned alkali, more preferably 0.9-3 mole.
Relative to 1 mole compound (VI), the preferred 0.8-5 mole of usage quantity of compound (LVI) or compound (LVII), more preferably 0.9-3 mole.
The temperature of reaction that compound (VI) and compound (LVI) or compound (LVII) react preferably-78 to 150 DEG C, more preferably 0-50 DEG C.
The reaction times that compound (VI) reacts from compound (LVI) or compound (LVII) is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(step 19)
The oxidizing reaction of compound (VII) normally makes compound (VII) and oxidant reaction carry out in a solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, methylene dichloride, chloroform, tetracol phenixin, 1, the halons such as 2-ethylene dichloride, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1, the alkyl such as ethers or the acetonitrile nitriles such as 4-diox, trifluoroacetic acid, pyridine, acetone etc., also can use their mixed solvent.
Above-mentioned oxygenant such as can be enumerated: the reagent that Manganse Dioxide, sulfur trioxide-pyridine, active dimethyl sulfoxide (DMSO) or Dai Si-Martin reagent etc. are commercially available.
Relative to 1 mole compound (VII), the preferred 0.5-3 mole of usage quantity of above-mentioned oxygenant, more preferably 0.8-2 mole.
The temperature of reaction of above-mentioned oxidizing reaction is different according to the kind of oxygenant, preferably-78 DEG C to 100 DEG C, more preferably-78 DEG C to 40 DEG C.
The reaction times of above-mentioned oxidizing reaction is different according to the reaction conditions such as kind, temperature of reaction of oxygenant, preferably 5 minutes-72 hours, more preferably 1-24 hour.
(manufacture method 13: the manufacture method of midbody compound (IX))
[changing 18]
[in formula, X
1for halogen atom, PG is the blocking group such as methyl or benzyl, R
12for alkoxyl groups etc. such as methoxy or ethoxies, other each symbol is identical with implication defined above].
Compound (IX) obtains by making compound (VIII) and compound (LVIII) react.Compound (VIII) and compound (LVIII) can utilize commercially available compound, also can synthesize according to method known in those skilled in the art.
(step 20)
The reaction of compound (VIII) and compound (LVIII) is normally carried out in dehydrated solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, diethyl ether, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: lithium diisopropyl amido, two (trimethyl silyl) amido lithium or two (trimethyl silyl) amido potassium.
Relative to 1 mole compound (VIII), the preferred 0.8-4 mole of usage quantity of above-mentioned alkali, more preferably 0.9-3.5 mole.
Relative to 1 mole compound (VIII), the preferred 0.8-5 mole of usage quantity of compound (LVIII), more preferably 0.9-3 mole.
The temperature of reaction that compound (VIII) and compound (LVIII) react preferably-78 to 150 DEG C, more preferably 0-50 DEG C.
The reaction times that compound (VIII) reacts from compound (LVIII) is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(manufacture method 14: the manufacture method of midbody compound (XI))
[changing 19]
[in formula, each symbol is identical with implication defined above].
Compound (XI) is reduced by compound (IX), then by gained compound (X) oxidation is obtained.
(step 21)
The reduction reaction of compound (IX) normally makes compound (IX) and reductive agent react to carry out in a solvent, suitably can select the solvent not hindering reaction.The solvent of reaction is not hindered to enumerate: the hydro carbons such as octane, hexane, benzene, toluene, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, glycol dimethyl ether, diethyl ether, or the alcohols such as methyl alcohol, ethanol, Virahol, also can use their mixed solvent.
Above-mentioned reductive agent such as can be enumerated: lithium borohydride, diisobutyl aluminium hydride, lithium aluminum hydride, triethyl lithium hydride, two (2-methoxy ethoxy) sodium aluminum hydride or borane complex.
Relative to 1 mole compound (IX), the preferred 0.25-100 mole of usage quantity of above-mentioned reductive agent, more preferably 0.5-20 mole.
The temperature of reaction of above-mentioned reduction reaction preferably-78 to 150 DEG C, more preferably-78 to 100 DEG C.
The reaction times of above-mentioned reduction reaction is different according to the reaction conditions of the amount of temperature of reaction, reductive agent etc., preferably 5 minutes-72 hours, more preferably 30 minutes-24 hours.
(step 22)
The oxidizing reaction of compound (X) normally makes compound (X) and oxidant reaction carry out in a solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as trifluoroacetic acid, pyridine, acetone, octane, hexane, benzene, toluene, methylene dichloride, chloroform, tetracol phenixin, 1, the halons such as 2-ethylene dichloride, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1, the alkyl such as ethers or the acetonitrile nitriles such as 4-diox, also can use their mixed solvent.
Above-mentioned oxygenant such as can be enumerated: the reagent that sulfur trioxide-pyridine, active dimethyl sulfoxide (DMSO) or Dai Si-Martin reagent etc. are commercially available.
Relative to 1 mole compound (X), the preferred 0.5-3 mole of usage quantity of above-mentioned oxygenant, more preferably 0.8-2 mole.
The temperature of reaction of above-mentioned oxidizing reaction is different according to the kind of oxygenant, preferably-78 to 100 DEG C, more preferably-78 to 40 DEG C.
The reaction times of above-mentioned oxidizing reaction is different according to the reaction conditions such as kind, temperature of reaction of oxygenant, preferably 5 minutes-72 hours, more preferably 1-24 hour.
(manufacture method 15: the manufacture method of midbody compound (XII))
[changing 20]
[in formula, each symbol is identical with implication defined above].
(step 23)
Compound (XII) is by being transformed to alkynes to obtain by compound (XI).The reagent used in above-mentioned transformationreation such as can enumerate 1-diazo-2-oxopropyl dimethyl phosphonate.Above-mentioned transformationreation can be carried out according to the method for known document (Tetrahedron Letters, 47 volumes, 1729-1731 page in 2006) or the method based on it.
(manufacture method 16: the manufacture method of midbody compound (SIIb))
[changing 21]
[in formula, each symbol is identical with implication defined above].
Compound (SIIb) is that compound (XII) and compound (LVI) are reacted, then by gained compound (XIII) oxidation is obtained.Compound (SIIb) also obtains by making compound (LVII) and compound (XII) react.Compound (LVI) and compound (LVII) can utilize commercially available compound, also can synthesize according to method known in those skilled in the art.
(step 24 or step 25)
The nucleophilic addition of compound (XII) normally carries out in dehydrated solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as octane, hexane, benzene, toluene, the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, ethylene glycol dimethyl ether, diethyl ether, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: the lithium alkylide such as lithium methide, n-Butyl Lithium class, the salt of the dialkyl amines such as lithium diisopropyl amido, two (trimethyl silyl) amido lithium, two (trimethyl silyl) amido potassium.
Relative to 1 mole compound (XII), the preferred 0.8-5 mole of usage quantity of above-mentioned alkali, more preferably 0.9-3 mole.
Relative to 1 mole compound (XII), the preferred 0.8-5 mole of usage quantity of compound (LVI) or compound (LVII), more preferably 0.9-3 mole.
The temperature of reaction of above-mentioned nucleophilic addition preferably-78 to 150 DEG C, more preferably 0-50 DEG C.
The reaction times of above-mentioned nucleophilic addition is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(step 26)
The oxidizing reaction of compound (XIII) normally makes compound (XIII) and oxidant reaction carry out in a solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the hydro carbons such as trifluoroacetic acid, pyridine, acetone, octane, hexane, benzene, toluene, methylene dichloride, chloroform, tetracol phenixin, 1, the halons such as 2-ethylene dichloride, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1, the alkyl such as ethers or the acetonitrile nitriles such as 4-diox, also can use their mixed solvent.
Above-mentioned oxygenant such as can be enumerated: the reagent that Manganse Dioxide, sulfur trioxide-pyridine, active dimethyl sulfoxide (DMSO) or Dai Si-Martin reagent etc. are commercially available.
Relative to 1 mole compound (XIII) 1 mole, the preferred 0.5-3 mole of usage quantity of above-mentioned oxygenant, more preferably 0.8-2 mole.
The temperature of reaction of above-mentioned oxidizing reaction is different according to the kind of oxygenant, preferably-78 to 100 DEG C, more preferably-78 to 40 DEG C.
The reaction times of above-mentioned oxidizing reaction is different according to the reaction conditions such as kind, temperature of reaction of oxygenant, preferably 5 minutes-72 hours, more preferably 1-24 hour.
(manufacture method 17: the manufacture method of midbody compound (SIIIa))
[changing 22]
[in formula, each symbol is identical with implication defined above].
Compound (SIIIa) obtains as follows: by compound (XIV) compound (LX) alkylation; or the compound (XVI) compound (LXI) obtained by compound (XIV) is carried out acylations, then by compound (XV) cyclisation of gained is obtained.Compound (XIV) and compound (LX) can synthesize according to method known in those skilled in the art.Compound (LXI) can utilize commercially available compound, also can synthesize according to method known in those skilled in the art.
(step 27)
The alkylated reaction of compound (XIV) normally makes compound (XIV) and halogenated alkyl react in solvent in the presence of a base to carry out, suitably can select the solvent not hindering reaction.The solvent of reaction is not hindered to enumerate: the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, ethylene glycol dimethyl ether, acetone, acetonitrile or DMF, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: the hydrogen-carbonate such as sodium bicarbonate, saleratus basic metal class, the alkali metal carbonate such as salt of wormwood, cesium carbonate class, amine, potassium tert.-butoxide or the sodium hydrides such as triethylamine, diisopropylethylamine, pyridine.
Relative to 1 mole compound (XIV), the preferred 0.5-6 mole of usage quantity of above-mentioned alkali, more preferably 0.8-3 mole.
Relative to 1 mole compound (XIV), the preferred 0.5-5 mole of usage quantity of compound (LX), more preferably 0.8-2 mole.
The temperature of reaction of abovementioned alkylization reaction preferably-78 to 200 DEG C, more preferably-20 to 100 DEG C.
The reaction times of abovementioned alkylization reaction is different according to reaction conditions, preferably 5 minutes-78 hours, more preferably 30 minutes-48 hours.
(step 28)
Compound (XVI) such as according to the method known in those skilled in the art using thionyl chloride or oxalyl chloride etc., can be synthesized by compound (XIV).
(step 29)
The acylation reaction of the compound (LXI) undertaken by compound (XVI) is normally carried out in solvent in the presence of a base, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the halons such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, the ethers such as tetrahydrofuran (THF), 1,2-glycol dimethyl ether, Isosorbide-5-Nitrae-diox, also can use their mixed solvent.
Above-mentioned alkali such as can be enumerated: pyridine, triethylamine, diisopropylethylamine or N, N-dimethyl aminopyridine etc.
Relative to 1 mole compound (XVI), the preferred 0.1-6 mole of usage quantity of above-mentioned alkali, more preferably 0.8-3 mole.
Relative to 1 mole compound (XVI), the preferred 0.5-3 mole of usage quantity of compound (LXI), more preferably 0.8-1.5 mole.
The temperature of reaction of above-mentioned acylation reaction preferably-20 to 150 DEG C, more preferably 0-100 DEG C.
The reaction times of above-mentioned acylation reaction is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(step 30)
Carry out in the cyclization of compound (XV) solvent normally under ammonium salt exists, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate acetic acid or formic acid, can use their mixed solvent yet.
Above-mentioned ammonium salt such as can be enumerated: the reagent that ammonium acetate, ammonium formiate or volatile salt etc. are commercially available.
Relative to 1 mole compound (XV), the preferred 1-20 mole of usage quantity of above-mentioned ammonium salt, more preferably 2-15 mole.
The preferred 0-200 DEG C of temperature of reaction of above-mentioned cyclization, more preferably 50-120 DEG C.
The reaction times of above-mentioned cyclization is different according to reaction conditions, preferably 5 minutes-100 hours, more preferably 30 minutes-48 hours.
(manufacture method 18: the manufacture method of midbody compound (SIIIb))
[changing 23]
[in formula, each symbol is identical with implication defined above].
Compound (SIIIb) obtains as follows: compound (XIV) is carried out amidation, gained compound (XVII) is proceeded thioamides, make compound (XVIII), then use compound (LX), obtained by cyclisation.Compound (XIV) can synthesize according to method known in those skilled in the art.Compound (LX) also can synthesize according to method known in those skilled in the art.
(step 31)
The amidate action of compound (XIV), normally in solvent in the presence of a base, uses chloro-formic ester etc. to form mixed acid anhydride, then makes ammoniacal liquor and its reaction carry out, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, ethylene glycol dimethyl ether, the halon such as methylene dichloride, chloroform or DMF, also can use their mixed solvent.
Above-mentioned chloro-formic ester such as can be enumerated: methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate or sec-butyl chloroformate.
Relative to 1 mole compound (XIV), the preferred 0.5-4 mole of usage quantity of above-mentioned chloro-formic ester, more preferably 0.9-2 mole.
Above-mentioned alkali such as can be enumerated: the organic basess such as the mineral alkalis such as sodium bicarbonate, sodium carbonate, salt of wormwood, cesium carbonate or triethylamine, diisopropylethylamine, pyridine.
Relative to 1 mole compound (XIV), the preferred 0.5-5 mole of usage quantity of above-mentioned alkali, more preferably 0.9-2.5 mole.
About the temperature of reaction of above-mentioned amidate action, for the formation of mixed acid anhydride, preferably-78 to 200 DEG C, more preferably-20 to 100 DEG C.About the reaction added after ammoniacal liquor, preferably-78 to 200 DEG C, more preferably-20 to 100 DEG C.
The reaction times of above-mentioned amidate action is different according to reaction conditions, for the formation of mixed acid anhydride, and preferably 5 minutes-48 hours, more preferably 30 minutes-24 hours.For the reaction added after ammoniacal liquor, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(step 32)
The thioamidesization reaction of compound (XVII) normally makes commercially available reagent react such as compound (XVII) and lawesson reagent or thiophosphoric anhydride etc. carry out in a solvent, suitably can select the solvent not hindering reaction.Do not hinder the solvent of reaction such as can enumerate: the stable hydrocarbon such as benzene, toluene, the halogen solvent such as methylene dichloride, chloroform or the ethers such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, also can use their mixed solvent.
Relative to 1 mole compound (XVII), the preferred 0.3-4 mole of usage quantity of above-mentioned lawesson reagent or thiophosphoric anhydride etc., more preferably 0.4-2 mole.
The temperature of reaction of above-mentioned thioamidesization reaction preferably-20 to 200 DEG C, more preferably 0-120 DEG C.
The reaction times of above-mentioned thioamidesization reaction is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
(step 33)
The cyclization of compound (XVIII) normally carries out suitable not hindering in the solvent of reaction of selection.Do not hinder the solvent of reaction such as can enumerate: the alcohols such as methyl alcohol, ethanol, ethers or the acetonitriles such as tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox, also can use their mixed solvent.
Relative to 1 mole compound (XVIII), the preferred 0.5-4 mole of usage quantity of compound (LX), more preferably 0.9-1.5 mole.
The temperature of reaction of above-mentioned cyclization preferably-20 to 200 DEG C, more preferably 0-100 DEG C.
The reaction times of above-mentioned cyclization is different according to reaction conditions, preferably 5 minutes-72 hours, more preferably 30 minutes-48 hours.
When compound (I) obtains with the form of episome, target salt can be transformed to according to known method or the method based on it, on the contrary, when obtaining in a salt form, can be episome or other target salt according to known method or the method migration based on it.
Compound (I) can be made prodrug and use, the prodrug of compound (I) such as can be enumerated: under the physiological condition in body, by the compound, namely that the reactions change of enzyme or hydrochloric acid in gastric juice etc. is compound (I), there are oxydasis, reduction, hydrolysis etc., be changed to the compound of compound (I); Cause hydrolysis etc. by hydrochloric acid in gastric juice etc., be changed to the compound of compound of the present invention (I); The compound that the hydroxyl generation acylations of compound (I), alkylation, phosphorylation, boration obtain.The preferred object lesson of the prodrug of compound (I) is as shown in table 2, but they do not limit the present invention.
[table 2]
The prodrug of compound (I) can be synthesized by compound of the present invention (I) according to known method.The prodrug of compound (I) can be in known document (" exploitations of pharmaceuticals ", Guang Chuan bookstore, nineteen ninety, 7th volume, 163-198 page and Prog.Med.5,, 2157-2161 page in 1985) described in physiological condition under be changed to the compound of compound (I).
Medicine containing compound (I), when to mammals administration beyond the mankind, also shows excellent result for the treatment of for retention of urine obstacle.Mammals beyond the mankind such as can be enumerated: mouse, rat, hamster, rabbit, cat, dog, ox, sheep, monkey etc.
The form of medication of compound (I) can be that compound (I) is direct or coordinate medicine acceptable carrier, oral or non-oral administration.
When oral administration contains the preparation of compound (I), formulation such as can be enumerated: tablet (comprising coated tablet, thin membrane coated tablet), pill, granule, powder, capsule (comprising soft capsule, microcapsule), syrup, emulsion, suspensoid, during non-oral administration, formulation such as can be enumerated: injection, injectant, some drops, suppository.Also can combine with suitable matrix (mixture, the polyglycerol fatty acid ester of the polymkeric substance of the polymkeric substance of such as butyric acid, the polymkeric substance of oxyacetic acid, the multipolymer of butyric acid-oxyacetic acid, the polymkeric substance of butyric acid and oxyacetic acid), make slow-releasing preparation, this is also effective.
The preparation of the preparation of the above-mentioned formulation containing compound (I) can be carried out according to the known manufacture method used conventional in formulation art.In this case, can manufacture containing the excipient, tackiness agent, lubricant, disintegrating agent, sweeting agent, tensio-active agent, suspension agent, emulsifying agent etc. used conventional in formulation art as required.
The preparation of the tablet containing compound (I) can contain excipient, tackiness agent, disintegrating agent, lubricant etc. to carry out, and the preparation of pill and granule can contain excipient, tackiness agent, disintegrating agent etc. and carry out.The preparation of powder and capsule can be carried out containing excipient etc., and the preparation of syrup can be carried out containing sweeting agent etc., and the preparation of emulsion or suspensoid can contain tensio-active agent, suspension agent, emulsifying agent etc. and carry out.
Above-mentioned excipient such as can be enumerated: lactose, glucose, starch, sucrose, Microcrystalline Cellulose, Radix Glycyrrhizae powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate.
Above-mentioned tackiness agent such as can be enumerated: starch pasting liquid, Sudan Gum-arabic liquid, gelatin solution, tragakanta liquid, carboxymethyl cellulose liquid, sodium alginate solution, glycerine.
Above-mentioned disintegrating agent such as can be enumerated: starch, calcium carbonate.
Above-mentioned lubricant such as can be enumerated: Magnesium Stearate, stearic acid, calcium stearate, Purified talc.
Above-mentioned Sweetening agents is as enumerated: glucose, fructose, Nulomoline, Sorbitol Powder, Xylitol, glycerine, simple syrup.
Above-mentioned tensio-active agent such as can be enumerated: Sodium Lauryl Sulphate BP/USP, poly-Sorbitol Powder 80, sorbitan mono fatty acid ester, polyoxyethylene stearic acid ester 40.
Above-mentioned suspending agents is as enumerated: Sudan Gum-arabic, sodium alginate, Xylo-Mucine, methylcellulose gum, wilkinite.
Mentioned emulsifier such as can be enumerated: Sudan Gum-arabic, western yellow alpine yarrow, gelatin, poly-Sorbitol Powder 80.
When the preparation containing compound (I) is prepared into above-mentioned formulation, the conventional tinting material, sanitas, perfume compound, correctives, stablizer, thickening material etc. used in formulation art can be added further.
Dosage every day of above-mentioned preparation is different from the kind, route of administration etc. of the state of patient or body weight, compound, such as during oral administration, if adult (body weight about 60 kg), then the preferred scope with 1 mg-1000 mg divides 1-3 administration, during non-oral administration, if injection, then the preferred scope with every 1 kg body weight 0.01-100 mg passes through intravenous administration.
Retention of urine obstacle refers to state or the symptom of the urine that cannot store substantial amount in bladder, specifically can enumerate: frequent micturition, the urinary incontinence, urgency etc.
Frequent micturition refers to the state that number of micturitions increases.Frequent micturition refers to frequent micturition on daytime, nocturnal pollakiuria, nervosa frequent micturition, psychogenic frequent micturition etc.
The urinary incontinence refers to the state that urine does not independently spill.The urinary incontinence can be enumerated: the abdominal pressure urinary incontinence, urge incontinence, mixed urinary incontinence, enuresis disease (daytime the enuresis, enuresis nocturna, nocturnal enuresis disease), the persistence urinary incontinence, overflow incontinence, the non-resistance urinary incontinence, REFLEX INCOMTINENCE, real urinary incontinence, FUNCTIONAL INCONTINENCE etc.
Urgency represents state that is that occur suddenly, strong, that present hard to bear strong urine meaning.Usually, bladder just can produce urine meaning when the urine retaining q.s, on the other hand, in the diseases such as overactive bladder, namely the urine of bladder produces unexpected, strong urine meaning not having under the state retained too much, causes being difficult to stand, the sensation that urine will spill.
Cause the disease of the retention of urine obstacles such as frequent micturition, the urinary incontinence or urgency such as can enumerate: neurogenic bladder dysfunction, overactive bladder, unstable bladder, cystospasm, chronic cystitis, interstitial cystitis, pain property bladder syndrome (painful bladder syndrome), chronic prostatitis, prostatomegaly or prostate cancer etc.
Neurogenic bladder dysfunction refers to: the nerve arranging the lower urethra formed by bladder, urethra and the musculus sphincter of external urethra is subject to certain obstacle, result, and abnormal state occurs for retention of urine, the mechanism of micturition of lower urethra.Here, the disease making the nerve of urethra under domination produce obstacle such as can be enumerated: cerebrovascular disorder, cerebral tumor, cerebral trauma, encephalitis, cerebral tumor, normal pressure hydrocephalus, dull-witted, Parkinson's disease, dysthymia disorders, nigrostriatal degeneration disease, Xing Ma Paralysis on Progressive symmetric erythrokeratodermia core, olivopontocerebellar atrophy, Shy-Drager syndrome, Spinal injury, spinal cord vascular disease, tumor of spinal cord, myelitis, the repressive disease of cervical vertebra, syringomyelia, (myelencephalon) multiple sclerosis, spina bifida, meningomyelocele goes out, Taper Pipe stenosis, tethered cord syndrome (Tethered cord syndrome), myelopathy, diabetes or basin intracavity operation etc.
The interstitial that interstitial cystitis refers between urothelial and smooth muscle of bladder causes the disease of chronic inflammatory diseases for a certain reason.Cardinal symptom has: the retention of urine obstacles such as frequent micturition, the urinary incontinence, urgency and pain or unplessantness displeasure etc., particularly lower abdominal pain and urinate frequently when urinating, this symptom makes the QOL of patient (quality of life) significantly reduce.Once take various pharmacotherapy, but be showed no sufficient result for the treatment of.
Therapeutical agent or the preventive of retention of urine obstacle of the present invention have analgesic effect concurrently, are therefore preferred for the situation of retention of urine obstacle with pain.Cause in the disease of retention of urine obstacle, the disease with pain comprises the diseases associated with inflammation causing retention of urine obstacle, such as, can enumerate: chronic cystitis, interstitial cystitis, pain property bladder syndrome (painful bladder syndrome) etc.The therapeutical agent of further preferred retention of urine obstacle of the present invention or preventive are used for interstitial cystitis.
The therapeutical agent of retention of urine obstacle of the present invention or preventive also or can cause the therapeutical agent of the disease of retention of urine obstacle or preventive to combinationally use with the therapeutical agent of other retention of urine obstacle or preventive.
Therapeutical agent or the preventive of other retention of urine obstacle such as can be enumerated: Propanthelinium (Propantheline), Oxybutynin (Oxybutynin), Propiverine (Propiverine), tolterodine (Tolterodine), temiverine (Temiverine), trospium chloride (Trospium), darifenacin (Darifenacin), Solifenacin (Solifenacin), the anticholinergic drugs such as KRP-197, the smooth muscle relaxants such as flavoxate (Flavoxate), NS-8, ZD-0947, KW-7158, ABT-598, the potassium channel openerses such as WAY-151616, nifedipine (Nifedipine), the calcium-channel antagonists such as flunarizine (Flunarizine), baclofen (Baclofen), diazepam (Diazepam), the skeletal muscular relaxants such as Lanperisone (Lanperisone), imipramine (Imipramine), Desipramine (Desipramine), fluoxetine (Fluoxetine), fluvoxamine (Fluvoxamine), Midalcipran (Milnacipran), paroxetine (Paroxetine), the thymoleptic such as duloxetine (Duloxetine), the vassopressin agonists such as deammoniation argipressin (Desmopressin), TAK-637, SR-48968, the tachykinin antagenists such as Talnetant (Talnetant), clenbuterol (Clenbuterol), KUC-7483, YM-178, the beta-agonists such as GW-427353, capsaicine, vanilla aldehydes (vanilloid) agonists such as resiniferatoxin (resiniferatoxin), SB-705498, AMG-0347, BCTC, A-784168, SPM-955, the vanilla aldehydes antagonists such as DD-161515, ONO-8711, the PGE antagonists such as ONO-8992, the COX inhibitor such as U-27182 (Flurbiprofen), the α such as R-450 1 agonist, Doxazosin (Doxazosin), Indoramine (Indoramin), terazosin (Terazosin), ebrantill (Urapidil), alfuzosin (Alfuzosin), Prazosin (Prazosin), naftopidil (Naftopidil), tamsulosin (Tamsulosin), セ ロ De シ Application (Selodosin), fiduxosin (Fiduxosin), the α such as KMD-3213 1 antagonist or vinpocetin (Vinpocetine), GW-286103, zonisamide (Zonisamide), mexiletine (Mexiletine), ranolazine (Ranolazine), the sodium channel inhibitor etc. such as Riluzole (Riluzole).
Cause the disease of retention of urine obstacle such as can enumerate: prostate hyperplasia, prostate cancer, diabetes, cerebrovascular disorder, the dementia comprising alzheimer's disease, dysthymia disorders, Parkinson's disease or (spinal cord) multiple sclerosis etc.
The therapeutical agent of prostate hyperplasia or preventive such as can be enumerated: finasteride (Finasteride), dutasteride (Dutasteride), izonsteride (Izonsteride), CS-891, the 5α-reductase inhibitor such as MK-434, flutamide (Flutamide), bicalutamide (Bicalutamide), the androgen receptor antagonists such as Nilutamide (Nilutamide), Allyloestrenol (Allylestrenol), Verton (Chlormadinone), Gestonorone (Gestonorone), cyproterone (Cyproterone), Ao Shatelong (Osaterone), the antiandrogens such as Nomegestrol (Nomegestrol), SB-217242, the endothelin antagonists such as TA-0201, urine is logical, the vegetalitas preparations such as Prostat or above-mentioned α 1 antagonist etc.
The therapeutical agent of prostate cancer or preventive such as can be enumerated: the LH-RH agonists such as Leuprolide (Leuprorelin), goserelin (Goserelin), buserelin (Buserelin), nafarelin (Nafarelin), triptorelin (Triptorelin), the LH-RH antagonistics such as cetrorelix (Cetrorelix), Ganirelix (Ganirelix), abarelix (Abarelix), above-mentioned 5α-reductase inhibitor, above-mentioned androgen receptor antagonists or above-mentioned antiandrogen etc.
The therapeutical agent of diabetes or preventive such as can be enumerated: pioglitazone (Pioglitazone), troglitazone (Troglitazone), the insulin resistances such as Rosiglitazone (Rosiglitazone) improve medicine, tolbutamide (Tolbutamide), P-607 (Chlorpropamide), tolazamide (Tolazamide), acetohexamide (Acetohezamide), glyclopyramide (Glyclopyramide), Glyburide (Glibenclamide), gliclazide (Gliclazide), glimepiride (Glimepiride), repaglinide (Repaglinide), the insulin secretions such as nateglinide (Nateglinide) promote medicine, N1,N1-Dimethylbiguanide (Metformin), the biguanides medicines such as buformin (Buformin), Regular Insulin, acarbose (Acarbose), voglibose (Voglibose), miglitol (Miglitol), the alpha-glucosaccharase enzyme inhibitors such as emiglitate (Emiglitate), AJ-9677, SR-58611-A, SB-226552, the β such as AZ40140 3 adrenoceptor agonists, エ ロ go セ ッ ト (Erogoset), tripro-amylin (Pramlintide), Leptin (Leptin) or BAY-27-9955 etc.
The therapeutical agent of cerebrovascular disorder or preventive such as can be enumerated: aniracetam (Aniracetam), Ibudilast (Ibudilast), tiapride (Tiapride), カ Le ジ オ ク ロ ー system (Cardiocrome), citicoline (Citicoline), γ-aminobutyric acid (γ-aminobutyric acid), ifenprodil (Ifenprodil), nicergoline (Nicergoline), vinpocetin (Vinpocetine), nizofenone (Nizofenone), bencyclane (Bencyclane), cinepazide (Cinepazide) etc.
The therapeutical agent or the preventive that comprise the dementia of alzheimer's disease such as can be enumerated: E2020 (Donepezil), memantine (Memantine), lycoremine (Galantamine) etc.
The therapeutical agent of dysthymia disorders or preventive such as can enumerate above-mentioned thymoleptic etc.
Parkinsonian therapeutical agent or preventive such as can be enumerated: amantadine (Amantadine), Trihexyphenidyl (Trihexyphenidyl), bromocriptine (Bromocriptine), levodopa (Levodopa), carbidopa (Carbidopa), Apomorphine (Apomorphine) etc.
Therapeutical agent or the preventive of (spinal cord) multiple sclerosis such as can be enumerated: steroid dose, interleukin--β-1b(Interferon-β-1b) etc.
Embodiment
Below, illustrate the present invention according to embodiment, but the present invention is not limited thereto.
(effect for Induced by Cyclophosphamide frequent micturition rat model)
Experiment is the SD system female rats using 7-11 age in week, often organizes 6-7 example.Give rat by endoxan (SIGMA) (150 mg/kg) intraperitoneal, make frequent micturition model people such as (, British journal of pharmacology., the 130th volume, 331 pages in 2000) Lecci A thus.Can think that this model can effectively as the frequent micturition model of model, the particularly interstitial cystitis of the retention of urine obstacle with diseases associated with inflammation.After giving endoxan 4-5 hour, give carbamate (1 g/kg) by intraperitoneal and anesthesia is implemented to frequent micturition rat model, then implement small incision surgery at its abdomen, ligation both sides ureter, small incision surgery is implemented to the ureter of kidney side.Then, otomy is implemented to the bladder top of frequent micturition rat model, insert the polyethylene hose indwelling that are full of physiological saline.The other end of this flexible pipe via three-way cock, a side with as cystomanometry with pressure transmitter (Japanese photoelectricity manufacture) be connected, the opposing party with inject as intravesical physiological saline with lasting implanter be connected.
After above-mentioned operation terminates 30 minutes, continue saline injection (3.6 mL/ hour) to intravesical, obtain continuous print intravesical pressure curve (Cystometrograms thus; Hereinafter referred to as CMGs).After confirming that CMGs is stable, by tail intravenously administrable testing compound solution or its solvent.Before and after the administration obtaining testing compound group, the velocity of variation of number of micturitions, compares with group of solvents.
It is 10 mg/mL concentration that testing compound solution is prepared into test compounds substrate concentration, carries out intravenous administration (5 mg/kg) with the administration capacity of 1 kg body weight 0.5 mL.The solvent of testing compound solution uses dimethyl sulfoxide (DMSO) (hereinafter referred to as DMSO): Tween80: physiological saline (1:1:8).
Number of micturitions is measured according to CMGs.With the administration testing compound number of micturitions of first 20 minutes for 100%, the number of micturitions of 20 minutes after administration testing compound is represented with %, it can be used as the velocity of variation of number of micturitions.Statistical procedures is undertaken by the t inspection of non-corresponding.
Result as shown in Figure 1.The longitudinal axis represents the velocity of variation (mean+/-standard error, N=6-7) of number of micturitions.* in figure represented in the comparing of the group of solvents (in figure " solvent " group) with frequent micturition rat model, and had significant difference (*: p < 0.05) statistically.
During with 5 mg/kg intravenous administration compound 3, compare with group of solvents, the increase of the number of micturitions seen in frequent micturition rat model has and improves significantly.This result shows, and the compound (I) with hexanaphthene skeleton is effective for retention of urine obstacle.
(with the associativity of people's M-ChR)
Use express respectively people muscarine M1,2,3,4, the Chinese hamster ovary celI of 5 acceptors people such as (, Mol Pharmacol., the 35th No. 4, volume, 469-476 page in 1989) Buckley NJ.Receptor Binding Assay is conventionally implemented (people such as Luthin GR, Pharmacol Exp Ther., the 228th volume, No. 3,648-655 page in 1984).Radioactive mark ligand use 0.8 nmol/L [
3h] N-epoxytropine tropate, non-specific ligand use 1 μm of ol/L coromegine.Table 3 represents the inhibiting rate that compound 3 brings with radioactive mark ligand's specific binding of M-ChR.
[table 3]
Compound 3 shows, and does not all combine for anyone muscarinic receptor subtype.Shown by this result, the compound (I) with hexanaphthene skeleton there will not be the side effect based on cholinolytic effect to show.
(effect for pain)
Use can evaluate the mouse acetic acid twisting model of pain, the analgesic effect of assessing compound (I).
Make 5-6 week DDY system male mice fasting in age 16 hours, raise under free conditions of water drinking, oral administration testing compound solution or its solvent (10 mL/kg).The solvent of testing compound solution uses DMSO:Tween80: distilled water (1:1:8) or 27% hydroxypropyl-beta-cyclodextrin (hereinafter referred to as HP-β-CD).Administration is after 45 minutes, and intraperitoneal gives 0.6% acetum (10 mL/kg), brings out writhing response (behavior of body-stretching or twisting).Give acetum after 10 minutes, count the writhing response occurred in 10 minutes, using this number of times as the index of pain.
With the mean value of the writhing response number of times of group of solvents gained for 100%, now, by suppressed for this reaction 50% time the consumption of testing compound be expressed as ED
50.Result is as shown in table 4.
[table 4]
Solvent orange 2 A represents DMSO:Tween80: distilled water=1:1:8, and solvent B represents HP-β-CD.
In mouse acetic acid twisting model, the compound of table 4 all inhibits writhing response.This display compound (I) has analgesic effect.
The synthetic method of the raw material of compound (I) and intermediate and compound (I) is as described below.Here, for the compound used in intermediate synthesis, but do not describe the compound of synthetic method, use commercially available compound.
Solvent name in () that provide in NMR data represents the solvent used in mensuration.
400 MHz NMR spectrums are that the JNM-AL400 type nuclear magnetic resonance device using NEC to manufacture measures.Chemical shift take tetramethylsilane as benchmark, represent with δ (unit: ppm), signal represents with s (unimodal), d (bimodal), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), br (broad peak), dd (double doublet), dt (two triplet), ddd (three doublets), dq (two quartet), td (three doublets), tt (three triplets) respectively.The FT/IR-410 that IR spectrum uses Japanese light splitting society to manufacture measures, and the Micromass ZQ2K that ESI-MS spectrum uses Waters society to manufacture or the 1200LC/MSD that AgilentTechnology society manufactures measures.Solvent all adopts commercially available commodity.The YFLC W-prep2XY that flash column chromatography uses Shan Shan society to manufacture.
(compound 1)
According to 1-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexalin of following order synthesis as compound 1.
[changing 24]
At 4-p-methoxy-phenyl hydrazine hydrochloride (165 mg, 0.944 mmol) ethanol (5.0 mL) suspension in add triethylamine (258 μ L, 1.88 mmol), at room temperature stir 30 minutes, join 3-(1-hydroxy-cyclohexyl)-1-p-methylphenyl-2-propine-1-ketone (intermediate 8) (214 mg, 0.883 mmol) ethanol (3.0 mL) solution in, at room temperature stir 20 hours.Concentrating under reduced pressure reaction solution, adds distilled water in resistates, is extracted with ethyl acetate.Use anhydrous magnesium sulfate drying organic layer, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 1 (141 mg, 0.389 mmol, 44%) with the form of yellow non-crystalline.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.31-1.42?(1H,?m),?1.54-2.03?(9H,?m),?2.33?(3H,?s),?2.52?(1H,?brs),?3.81?(3H,?s),?6.40?(1H,?s),?6.84?(2H,?d,?J=8.8?Hz),?7.09?(4H,?s),?7.21?(2H,?d,?J=8.8?Hz)。
(compound 2 and compound 3)
According to 1-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-anti-form-1 of following order synthesis as compound 2,4-glycol
[changing 25]
With 1-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol as compound 3.
[changing 26]
At 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-1-ketone (compound 4) (8.00 g, 21.3 mmol) methyl alcohol (200 mL) solution in add sodium borohydride (804 mg, 21.3 mmol), at room temperature carry out stirring for 2 hours, be then injected in 1 M hydrochloric acid.Reaction solution is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 2 (1.66g as a white solid respectively, 4.39 mmol, 21%) and compound 3 (4.85g, 12.8 mmol, 60%).
Compound 2:
1h-NMR (400 MHz, CDCl
3) δ: 1.36 (1H, d, J=3.6 Hz), 1.64-1.72 (2H, m), 1.77-1.83 (2H, m), 2.04-2.12 (2H, m), 2.32-2.39 (5H, m), 2.56 (1H, s), 3.81 (3H, s), 4.03-4.06 (1H, m), 6.43 (1H, s), 6.85 (2H, d, J=8.8 Hz), 7.10 (4H, s), 7.21 (2H, d, J=8.8 Hz).
IR?(KBr,?cm
-1):?3344,?2929,?2875,?1740,?1516,?1443,?1369,?1251,?1032,?1001,?832.
ESI-MS:?m/z=?379?(M+H)
+
Mp?151-153℃
Anal.?Calcd?for?C23H26N2O3:?C,?72.99;?H,?6.92;?N,?7.40.?found:?C,?72.97;?H,?6.92;?N,?7.34
Compound 3:
1h-NMR (400 MHz, CDCl
3) δ: 1.44 (1H, s), 1.81-1.99 (6H, m), 2.04-2.12 (2H, m), 2.33 (3H, s), 2.56 (1H, s), 3.70-3.77 (1H, m), 3.80 (3H, s), 6.37 (1H, s), 6.85 (2H, d, J=8.8 Hz), 7.09 (4H, s), 7.20 (2H, d, J=8.8 Hz).
IR?(KBr,?cm
-1):?3303,?2918,?1517,?1442,?1366,?1248,?1063,?1026,?837,?807.
ESI-MS:?m/z=?379?(M+H)
+
Mp?164-166?℃
Anal.?Calcd?for?C23H26N2O3:?C,?72.99;?H,?6.92;?N,?7.40.?found:?C,?72.87;?H,?6.86;?N,?7.22。
(compound 5 and compound 22)
According to 1-(1-(4-the chloro-phenyl-)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-anti-form-1 of following order synthesis as compound 5,4-glycol,
[changing 27]
With 1-(1-(4-the chloro-phenyl-)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol as compound 22.
[changing 28]
At 4-hydroxyl-4-(1-(4-chloro-phenyl-)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-1-ketone (intermediate 65) (510 mg, 1.34 mmol) methyl alcohol (13 mL) solution in add sodium borohydride (53 mg, 1.40 mmol), at room temperature carry out stirring for 2 hours.Concentrating under reduced pressure reaction solution, is then dissolved in ethyl acetate, with distilled water, salt water washing.By organic over anhydrous dried over sodium sulfate, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 5 (114 mg as a white solid respectively, 0.298 mmol, 22%) and compound 22 (360 mg, 0.940 mmol, 70%).
Compound 5:
1h-NMR (400 MHz, CDCl
3) δ: 1.36 (1H, br), 1.65-1.72 (2H, m), 1.77-1.82 (2H, m), 2.04-2.11 (2H, m), 2.31-2.38 (2H, m), 2.36 (3H, s), 2.51 (1H, s), 4.03-4.08 (1H, m), 6.44 (1H, s), 7.10 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz), 7.22-7.30 (4H, m).
IR?(KBr,?cm
-1):?3349,?2918,?1497,?1440,?1366,?1240,?1098,?1007,?969,?833,?810.
ESI-MS:?m/z=?383?(M+H)
+
Compound 22:
1h-NMR (400 MHz, CDCl
3) δ: 1.45 (1H, br), 1.80-1.99 (6H, m), 2.03-2.07 (2H, m), 2.35 (3H, s), 2.51 (1H, s), 3.70-3.80 (1H, m), 6.39 (1H, s), 7.09 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 7.21-7.24 (2H, m), 7.27-7.31 (2H, m).
IR?(KBr,?cm
-1):?3365,?2946,?1496,?1442,?1368,?1241,?1095,?1059,?1014,?970,?887.
ESI-MS:?m/z=?365?(M-OH)
+。
(compound 6 and compound 8)
According to 1-(1,5-two (4-the p-methoxy-phenyl)-1H-pyrazole-3-yl) hexanaphthene-anti-form-1 of following order synthesis as compound 6,4-glycol,
[changing 29]
With 1-(two (4-the p-methoxy-phenyl)-1H-pyrazole-3-yl of 1, the 5-) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol as compound 8.
[changing 30]
At 4-(1, two (4-the p-methoxy-phenyl)-1H-pyrazole-3-yl of 5-)-4-hydroxy-cyclohexan alkane-1-ketone (intermediate 63) (523 mg, 1.38 mmol) methanol solution in add sodium borohydride (65 mg, 1.7 mmol), at room temperature stir 1.5 hours, concentrating under reduced pressure.In resistates, add distilled water, be extracted with ethyl acetate.By organic over anhydrous dried over mgso, concentrating under reduced pressure.By resistates flash column chromatography, be separated into low polarity component and high polar component.By low polarity component by recrystallization (ethyl acetate/normal hexane=2/1) purifying, obtain compound 6 (79 mg, 0.20 mmol, 14%) with the form of white crystal.By high polar component by recrystallization (ethyl acetate/normal hexane=2/1) purifying, obtain compound 8 (186 mg, 0.471 mmol, 34%) with the form of white crystal.
Compound 6:
1h-NMR (400 MHz, CDCl
3) δ: 1.33 (1H, d, J=3.4 Hz), 1.63-1.73 (2H, m), 1.75-1.84 (2H, m), 2.03-2.13 (2H, m), 2.30-2.39 (2H, m), 2.55 (1H, s), 3.80 (3H, s), 3.81 (3H, s), 4.02-4.08 (1H, m), 6.40 (1H, s), 6.82 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz).
IR?(KBr,?cm
-1):?3379,?1613,?1517,?1503,?1251,?1180,?1032,?1001,?835.
ESI-MS:?m/z=?395?(M+H)
+
Compound 8:
1h-NMR (400 MHz, CDCl
3) δ: 1.41 (1H, d, J=4.1 Hz), 1.79-2.55 (8H, m), 2.55 (1H, s), 3.69-3.78 (1H, m), 3.80 (3H, s), 3.81 (3H, s), 6.34 (1H, s), 6.81 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz), 7.20 (2H, d, J=8.8 Hz).
IR?(KBr,?cm
-1):?3385,?1613,?1517,?1503,?1250,?1064,?1031,?970,?835.
ESI-MS:?m/z=?395?(M+H)
+。
(compound 7 and compound 21)
According to 1-(5-(4-chloro-phenyl-)-1-(4-the p-methoxy-phenyl)-1H-pyrazole-3-yl) hexanaphthene-anti-form-1 of following order synthesis as compound 7,4-glycol,
[changing 31]
With 1-(5-(4-chloro-phenyl-)-1-(4-the p-methoxy-phenyl)-1H-pyrazole-3-yl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol as compound 21.
[changing 32]
At 4-(5-(4-chloro-phenyl-)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl)-4-hydroxy-cyclohexan alkane-1-ketone (intermediate 64) (619 mg, 1.56 mmol) methyl alcohol (15.6 mL) solution in add sodium borohydride (59.0 mg, 1.56 mmol), at room temperature carry out stirring for 1 hour, be then injected in 1 M hydrochloric acid.Reaction solution is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 7 (131 mg as a white solid respectively, 0.328 mmol, 21%) and compound 21 (291 mg, 0.730 mmol, 47%).
Compound 7:
1h-NMR (400 MHz, CDCl
3) δ: 1.32 (1H, d, J=3.2 Hz), 1.63-1.73 (2H, m), 1.76-1.84 (2H, m), 2.03-2.12 (2H, m), 2.30-2.39 (2H, m), 2.50 (1H, s), 3.82 (3H, s), 4.02-4.09 (1H, m), 6.46 (1H, s), 6.84-6.87 (2H, m), 7.14 (2H, d, J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), (7.26-7.28 2H, m).
ESI-MS:?m/z=?399?(M+H)
+
Compound 21:
1h-NMR (400 MHz, CDCl
3) δ: 1.41 (1H, d, J=5.2 Hz), 1.82-2.09 (8H, m), 2.49 (1H, s), 3.70-3.78 (1H, s), 3.82 (3H, s), 6.41 (1H, s), 6.85-6.87 (2H, m), 7.13 (2H, d, J=8.4 Hz), 7.18 (2H, d, J=8.4 Hz), 7.25-7.27 (2H, m).
ESI-MS:?m/z=?399?(M+H)
+。
(compound 9)
According to 1-(4-chloro-1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol of following order synthesis as compound 9.
[changing 33]
At acetic acid 4-(the chloro-1-of 4-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-c-4-hydroxy-cyclohexan alkane-r-1-base ester (intermediate 81) (67 mg, 0.147 mmol) methyl alcohol (1.5 mL) solution in add salt of wormwood (102 mg, 0.736 mmol), at room temperature stir 2 hours.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 9 (58 mg, 0.140 mmol, 95%) as a white solid.
1H-NMR?(400MHz,?CDCl
3)δ:?1.45?(1H,?s),?1.83-2.05?(6H,?m),?2.21-2.23?(2H,?m),?2.36?(3H,?s),?3.04?(1H,?s),?3.76-3.79?(4H,?m),?6.79-6.83?(2H,?m),?7.11-7.16?(6H,?m).
ESI-MS:?m/z=?395,?397?(M-OH)
+。
(compound 10)
According to 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-4-(trifluoromethyl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol of following order synthesis as compound 10
[changing 34]
At 0 DEG C, at 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-1-ketone (compound 4) (620 mg, 1.65 mmol) tetrahydrofuran (THF) (6.60 mL) solution in add (trifluoromethyl) trimethyl silane (535 μ L, 3.62 mmol), then tetra-n-butyl Neutral ammonium fluoride (TBAF is dripped, 1 M tetrahydrofuran solution) (362 μ L, 0.36 mmol), at room temperature stir 6 hours.In reaction solution, add tetra-n-butyl Neutral ammonium fluoride (TBAF, 1 M tetrahydrofuran solution) (3.29 mL, 3.29 mmol), at room temperature carry out stirring for 1 hour, be then injected in 1 M hydrochloric acid.By reaction solution diethyl ether.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 10 (410 mg, 0.92 mmol, 56%) as a white solid.
1H-NMR?(400MHz,?CDCl
3)?δ:?1.60?(1H,?s),?1.87-2.02?(4H,?m),?2.09-2.02?(2H,?m),?2.34-2.40?(6H,?m),?3.82?(3H,?s),?6.47?(1H,?s),?6.86?(2H,?d,?J=8.8?Hz),?7.08-7.11?(4H,?m),?7.20?(2H,?d,?J=8.8?Hz).
IR?(KBr,?cm
-1):?3402,?2954,?1517,?1463,?1305,?1250,?1249,?1179,?1121,?1056,?1024,?834.
ESI-MS:?m/z=?447?(M+H)
+。
(compound 11)
According to uncle-4-fluoro-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-alcohol of following order synthesis as compound 11
[changing 35]
Deoxofluor is added in methylene dichloride (1.19 mL) solution of acetic acid c-4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester (compound 12) (100 mg, 0.238 mmol)
tM(48 μ L, 0.262 mmol), at room temperature stirs 15 minutes.In reaction solution, add 1 M hydrochloric acid, use chloroform extraction.By organic layer washed with brine, then use anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain resistates.
In methyl alcohol (2.4 mL) solution of gained resistates, add salt of wormwood (164 mg, 1.18 mmol), at room temperature stir 2 hours.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 11 (22.4 mg, 0.058 mmol, 25%) as a white solid.
1H-NMR?(400MHz,?CDCl
3)δ:?1.37?(1H,?m),?1.72-1.77?(2H,?m),?2.02-2.14?(4H,?m),?2.34?(3H,?s),?2.38-2.49?(2H,?m),?3.81?(3H,?s),?4.11?(1H,?m),?6.52?(1H,?m),?6.84?(2H,?d,?J=8.8?Hz),?7.22?(2H,?d,?J=8.8?Hz),?7.26?(4H,?s).
ESI-MS:?m/z=?381?(M+H)
+。
(compound 12)
According to acetic acid c-4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester of following order synthesis as compound 12
[changing 36]
In 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-1,4-glycol (compound 3) (500 mg, 1.32 mmol) methylene dichloride (4.4 mL) suspension in add diacetyl oxide (0.312 mL, 3.30 mmol) with pyridine (0.267 mL, 3.30 mmol), 4-dimethylaminopyridine (16.1 mg, 0.132 mmol), at room temperature stir 45 minutes.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 12 (556 mg, 1.32 mmol, quantitative) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.89-2.08?(11H,?m),?2.34?(3H,?s),?2.64?(1H,?brs),?3.81?(3H,?s),?4.80-4.88?(1H,?m),?6.36?(1H,?s),?6.85?(2H,?d,?J=8.8?Hz),?7.00?(4H,?s),?7.20?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?421?(M+H)
+。
(compound 13)
According to 4-methoxyl group-1-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexalin of following order synthesis as compound 13
[changing 37]
At acetic acid c-4-methoxyl group-1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester (intermediate 39) (124 mg, 0.284 mmol) methyl alcohol (2.8 mL) solution in add salt of wormwood (197 mg, 1.42 mmol), at room temperature stir 18 hours.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 13 (102 mg, 0.260 mmol, 91%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.78-1.88?(2H,?m),?1.90-1.99?(4H,?m),?2.03-2.09?(2H,?m),?2.33?(3H,?s),?2.49?(1H,?s),?3.24-3.32?(1H,?m),?3.39?(3H,?s),?3.81?(3H,?s),?6.39?(1H,?s),?6.85?(2H,?d,?J=8.8?Hz),?7.09?(4H,?s),?7.20?(2H,?d,?J=8.8?Hz).
IR?(KBr,?cm
-1):?3425,?2937,?1516,?1443,?1369,?1300,?1249,?1171,?1099,?1030,?968,?834,?801.
ESI-MS:?m/z=?393?(M+H)
+。
(compound 14 and compound 20)
According to 4-(hydroxymethyl)-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-the pyrazole-3-yl)-anti-form-1 of following order synthesis as compound 14,4-hexalin (compound 14),
[changing 38]
With 4-(hydroxymethyl)-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-Isosorbide-5-Nitrae-hexalin (compound 20) as compound 20.
[changing 39]
At 4-(benzyloxymetliyl)-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-1-ketone (intermediate 51) (387 mg, 0.804 mmol) methyl alcohol (8.0 mL) solution in add sodium borohydride (30.4 mg, 0.804 mmol), at room temperature carry out stirring for 1 hour, be then injected in 1 M hydrochloric acid.Reaction solution is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain resistates.
Under a hydrogen atmosphere, in methyl alcohol (8.0 mL) solution of gained resistates, add 10% palladium on carbon (86.0 mg, 0.080 mmol), at room temperature stir 3 hours.Reaction solution is carried out diatomite filtration, concentrating under reduced pressure.By resistates flash column chromatography (amination silica gel, n-hexane/ethyl acetate) purifying, obtain compound 14 (51.6 mg as a white solid, 0.131 mmol, 16%), compound 20 (164 mg, 0.418 mmol, 52%) is obtained with the form that white is armorphous.
Compound 14:
1h-NMR (400 MHz, CDCl
3) δ: 1.43 (1H, brs), 1.54-1.67 (2H, m), 1.83-1.91 (4H, m), 2.00-2.08 (2H, m), 2.34 (3H, s), 3.24-3.33 (1H, m), 3.78-3.86 (6H, m), 6.32 (1H, s), 6.84 (2H, d, J=8.8 Hz), 7.10 (4H, s), 7.19 (2H, d, J=8.8 Hz).
ESI-MS:?m/z=?393?(M+H)
+
Compound 20:
1h-NMR (400 MHz, CDCl
3) δ: 1.39 (1H, d, J=4.8 Hz), 1.46-1.60 (4H, m), 1.85-1.95 (2H, m), 2.33-2.40 (5H, m), 2.71 (1H, t, J=6.4 Hz), 3.55 (2H, d, J=6.4 Hz), 3.71-3.83 (4H, m), 6.37 (1H, s), 6.85 (2H, d, J=8.8 Hz), 7.10 (4H, s), 7.20 (2H, d, J=8.8 Hz).
ESI-MS:?m/z=?393?(M+H)
+。
(compound 15)
According to 1-(1-(4-p-methoxy-phenyl)-5-(6-picoline-3-the base)-1H-pyrazole-3-yl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol of following order synthesis as compound 15.
[changing 40]
At 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-(6-picoline-3-base)-1H-pyrazole-3-yl)-hexanaphthene-1-ketone (intermediate 62) (109.5 mg, 0.29 mmol) methyl alcohol (1.5 mL) solution in add sodium borohydride (12.1 mg, 0.32 mmol), at room temperature carry out stirring for 40 minutes, then add 1 M hydrochloric acid.Reaction solution ethyl acetate is washed, water layer 1M-aqueous sodium hydroxide solution is made alkalescence, is extracted with ethyl acetate 2 times.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, ethyl acetate) purifying, obtain compound 15 (30.6 mg, 0.81 mmol, 28%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.59?(1H,?brs),?1.81-2.00?(6H,?m),?2.05-2.08?(2H,?m),?2.55?(3H,?s),?2.61?(1H,?s),?3.71-3.78?(1H,?m),?3.81?(3H,?s),?6.46?(1H,?s),?6.86?(2H,?d,?J=8.8?Hz),?7.06?(1H,?d,?J=8.0?Hz),?7.18?(2H,?d,?J=8.8?Hz),?7.32?(1H,?dd,?J=2.0,?8.0?Hz),?8.40?(1H,?d,?J=2.0?Hz).
IR?(KBr,?cm
-1):?3444,?2933,?2858,?1516,?1249,?1067,?968,?839.
ESI-MS:?m/z=?380?(M+H)
+。
(compound 16)
According to 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-naphthenic acid of following order synthesis as compound 16
[changing 41]
At c-4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-hexanaphthene-r-1-formaldehyde (intermediate 42) (124.9 mg, 0.32 mmol) the trimethyl carbinol (2.4 ml) solution in add distilled water (0.8 ml), 2-methyl-2-butene (101 μ l, 0.96 mmol), ice-cooled.At 0 DEG C, add SODIUM PHOSPHATE, MONOBASIC (42.1 mg, 0.35 mmol), clorox (72.3 mg, 0.80 mmol), stir 5 minutes.Be warming up to room temperature, stir 1 hour.Ice-cooledly then add Sulfothiorine to 0 DEG C, stir, add 1 M hydrochloric acid and ethyl acetate, extraction.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure, by resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 16 (116.6 mg as a white solid, 0.29 mmol, 93%).
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.87-2.11?(9H,?m),?2.33?(3H,?s),?2.40-2.43?(1H,?m),?3.81?(3H,?s),?6.38?(1H,?s),?6.84?(2H,?d,?J=9.2?Hz),?7.09-7.09?(4H,?m),?7.20?(2H,?d,?J=9.2?Hz).
IR?(KBr,?cm
-1):?3523,?2928,?1706,?1517,?1252,?831.
ESI-MS:?m/z=?407?(M+H)
+。
(compound 17)
According to 4,4-bis-fluoro-1-s (1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexalin of following order synthesis as compound 17
[changing 42]
At 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-4-oxo-cyclohexyl-1-yl acetate (intermediate 41) (110 mg, 0.263 mmol) methylene dichloride (2.63 mL) solution in add (dimethylamino) sulfur trifluoride (DAST) (104 μ L, 0.578 mmol), at room temperature stir 2 hours.In reaction solution, add 1 M hydrochloric acid, use chloroform extraction.By organic layer washed with brine, then use anhydrous magnesium sulfate drying, concentrating under reduced pressure, obtain resistates.
In the tetrahydrofuran (THF) (193 μ L) and methyl alcohol (386 μ L) solution of gained resistates, add 4 M aqueous sodium hydroxide solutions (193 μ L, 0.772 mmol), at room temperature stir 6 hours.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 17 (41.0 mg, 0.103 mmol, 39%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.01-2.31?(8H,?m),?2.34?(3H,?s),?2.77?(1H,?s),?3.81?(3H,?s),?6.37?(1H,?s),?6.86?(2H,?d,?J=8.8?Hz),?7.10?(4H,?s),?7.21?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?399?(M+H)
+。
According to the method same with the synthesis of above-claimed cpd 2 and compound 3, synthesize following compound.
[table 5-1]
[table 5-2]
[table 5-3]
[table 5-4]
(compound 41 and compound 42)
According to 1-(4-(4-the p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl) hexanaphthene-anti-form-1 of following order synthesis as compound 41,4-glycol,
[changing 43]
With 1-(4-(4-the p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol as compound 42.
[changing 44]
At 4-hydroxyl-4-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl) hexanaphthene-1-ketone (intermediate 83) (186 mg, 0.471 mmol) methyl alcohol (4.7 mL) solution in add sodium borohydride (36 mg, 0.943 mmol), at room temperature carry out stirring for 1 hour.Concentrating under reduced pressure reaction solution, is then dissolved in ethyl acetate, with distilled water, salt water washing.By organic over anhydrous dried over sodium sulfate, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 41 (42 mg as a white solid respectively, 0.106 mmol, 23%) and compound 42 (136 mg, 0.344 mmol, 73%).
Compound 41:
1h-NMR (400 MHz, CDCl
3) δ: 1.53-1.57 (1H, m), 1.76-1.87 (4H, m), 2.05-2.12 (2H, m), 2.35-2.42 (2H, m), 2.36 (3H, s), 3.15 (1H, br), 3.80 (3H, s), 4.10-4.14 (1H, m), 6.80-6.84 (2H, m), 7.13 (2H, d, J=8.0 Hz), 7.24 (2H, d, J=8.0 Hz), 7.45-7.49 (2H, m).
IR?(KBr,?cm
-1):?3409,?2923,?1613,?1515,?1252,?1179,?1004,?815.
ESI-MS:?m/z=?396?(M+H)
+
Compound 42:
1h-NMR (400 MHz, CDCl
3) δ: 1.48 (1H, d, J=4.8 Hz), 1.82-1.89 (2H, m), 1.95-2.01 (2H, m), 2.05-2.09 (4H, m), 2.36 (3H, s), 3.01 (1H, s), 3.76-3.82 (1H, m), 3.80 (3H, s), 6.80-6.83 (2H, m), 7.13 (2H, d, J=8.0 Hz), 7.22 (2H, d, J=8.0 Hz), (7.43-7.47 2H, m).
IR?(KBr,?cm
-1):?3418,?2938,?1611,?1515,?1249,?1177,?1058,?816.
ESI-MS:?m/z=?396?(M+H)
+。
(compound 43 and compound 44)
According to the synthesis of following order as compound 43 4-(two (the 4-p-methoxy-phenyl) oxazole-2-base) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol of 4,5-,
[changing 45]
With 4-(two (the 4-p-methoxy-phenyl) oxazole-2-base) hexanaphthene-anti-form-1 of 4,5-, the 4-glycol as compound 44.
[changing 46]
At 4-(4, two (4-p-methoxy-phenyl) oxazole-2-base)-4-hydroxycyclohexan-1-ketone (intermediate 82) (395 mg of 5-, 1.00 mmol) methyl alcohol (20 mL) solution in add sodium borohydride (47 mg, 1.24 mmol), at room temperature stir 16 hours.Concentrating under reduced pressure reaction solution, adds distilled water in resistates, is extracted with ethyl acetate.Use anhydrous magnesium sulfate drying organic layer, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 43 (207 mg as a white solid respectively, 0.523 mmol, 52%) and compound 44 (73 mg, 0.18 mmol, 18%).
Compound 43:
1h-NMR (400 MHz, CDCl
3) δ: 1.49 (1H, brs), 1.78-2.13 (8H, m), 2.76 (1H, s), 3.72-3.78 (1H, m), 3.83 (6H, s), 6.89 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.49 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz).
IR?(KBr,cm
-1):?3364,?1615,?1599,?1520,?1500,?1302,?1252,?1176,?1069,?1053,?1028,?965,?833.
ESI-MS:?m/z=?396?(M+H)
+
Compound 44:
1h-NMR (400 MHz, CDCl
3) δ: 1.63-1.75 (2H, m), 1.78-1.88 (2H, m), 2.01-2.12 (2H, m), 2.44-2.53 (2H, m), 2.67 (1H, s), 4.00-4.07 (1H, m), 6.89 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz).
IR?(KBr,cm
-1):?3356,?1613,?1600,?1520,?1503,?1254,?1182,?1033,?999,?966,?834.
ESI-MS:?m/z=?396?(M+H)
+。
(compound 45 and compound 46)
According to 1-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl)-4-(trifluoromethyl) hexanaphthene-anti-form-1 of following order synthesis as compound 45,4-glycol,
[changing 47]
With 1-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl)-4-(trifluoromethyl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol as compound 46.
[changing 48]
At room temperature, at 4-hydroxyl-4-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl) hexanaphthene-1-ketone (intermediate 83) (199 mg, 0.506 mmol) and Ruppert's reagent (0.187 mL, 1.26 mmol) tetrahydrofuran (THF) (2.5 mL) solution in add 1.0 M tetrabutyl ammonium fluoride/tetrahydrofuran solution (0.051 mL, 0.051 mmol), carry out stirring for 10 minutes.Concentrating under reduced pressure reaction solution, then tetrahydrofuran (THF) (3.0 mL) is dissolved in, add distilled water (0.2 mL) and 1.0 M tetrabutyl ammonium fluoride/tetrahydrofuran solution (1.02 mL, 1.02 mmol), at room temperature carry out stirring for 30 minutes.In reaction solution, add distilled water, be extracted with ethyl acetate, use salt water washing.By organic over anhydrous dried over sodium sulfate, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 45 (70 mg as a white solid respectively, 0.151 mmol, 30%) and compound 46 (132 mg, 0.285 mmol, 56%).
Compound 45:
1h-NMR (400 MHz, CDCl
3) δ: 1.79-1.84 (2H, m), 1.90 (1H, s), 1.96-2.01 (2H, m), 2.21-2.33 (4H, m), 2.37 (3H, s), 3.28 (1H, s), 3.80 (3H, s), 6.80-6.84 (2H, m), 7.13 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.0 Hz), 7.44-7.48 (2H, m).
IR?(KBr,?cm
-1):?3460,?2940,?1610,?1515,?1494,?1442,?1310,?1245,?1175,?1035,?1005,837,?813
ESI-MS:?m/z=?464?(M+H)
+
Compound 46:
1h-NMR (400 MHz, CDCl
3) δ: 1.90-1.96 (2H, m), 1.97 (1H, br), 2.16-2.23 (2H, m), 2.28-2.36 (4H, m), 2.37 (3H, s), 2.81 (1H, br), 3.80 (3H, s), 6.80-6.83 (2H, m), 7.14 (2H, d, J=8.0 Hz), 7.26 (2H, d, J=8.0 Hz), 7.44-7.48 (2H, m).
IR?(KBr,?cm
-1):?3419,?2940,?1611,?1515,?1443,?1290,?1250,?1175,?1120,?1066,?993,837,?814
ESI-MS:?m/z=?464?(M+H)
+。
According to the method same with the synthesis of above-claimed cpd 2 and compound 3, synthesize following compound.
[table 6-1]
[table 6-2]
[table 6-3]
(compound 58)
According to 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-naphthenic acid ethyl ester of following order synthesis as compound 58.
[changing 49]
At 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-naphthenic acid (compound 16) (41.6 mg, 0.10 mmol) DMF (1.0 ml) solution in add salt of wormwood (41.4 mg, 0.3 mmol) and iodoethane (24.8 μ l, 0.3 mmol), stir 2 hours.In reaction solution, add salt solution, be extracted with ethyl acetate.With salt water washing organic layer, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 58 (44.1 mg, 0.10 mmol, 97%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.27?(3H,?t,?J=6.8?Hz),?1.85-2.09?(8H,?m),?2.33?(3H,?s),?2.34-2.41?(1H,?m),?2.59?(1H,?s),?3.80?(3H,?s),?4.15?(2H,?q,?J=6.8?Hz),?6.38?(1H,?s),?6.84?(2H,?d,?J=8.8?Hz),?7.09-7.09?(4H,?m),?7.20?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?435?(M+H)
+。
For above-claimed cpd 3, synthesize its prodrug (compound 59-70).
(compound 59)
According to dimethyl carbamic acid 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl (compound 59) of following order synthesis as compound 59.
[changing 50]
Under ice-cooling, by tetrahydrofuran (THF) (6.0 ml) solution stirring 10 minutes of 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-Isosorbide-5-Nitrae-glycol (compound 3) (230 mg, 0.60 mmol).In reaction solution, add sodium hydride (26.4 mg, 0.66 mmol), stir 20 minutes at such a temperature, then drip dimethylcarbamyl chloride (84 μ l, 0.9 mmol).At room temperature stir 3 hours, then in reaction solution, add salt solution, be extracted with ethyl acetate.With salt water washing organic layer, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 59 (95.6 mg, 0.21 mmol, 35%) with faint yellow armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.93-2.04?(8H,?m),?2.33?(3H,?s),?2.71?(1H,?s),?2.92?(6H,?s),?3.80?(3H,?s),?4.73-4.79?(1H,?m),?6.37?(1H,?s),?6.84?(2H,?d,?J=8.8?Hz),?7.09-7.09?(4H,?m),?7.20?(2H,?J=8.8?Hz).
ESI-MS:?m/z=?450?(M+H)
+。
(compound 60)
According to 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl carbonic acid cyclohexyl (compound 60) of following order synthesis as compound 60.
[changing 51]
By 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-1,4-glycol (compound 3) (250 mg, 0.66 mmol) tetrahydrofuran (THF) (2.2 ml) solution ice cooling, add sodium hydride (63.4 mg, 1.45 mmol), stir 10 minutes at such a temperature.Add 1-iodine ethyl carbonate cyclohexyl (354 mg, 1.18 mmol), at room temperature stir 12 hours.In reaction solution, add salt solution, be extracted with ethyl acetate.With salt water washing organic layer, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 60 (161 mg, 0.29 mmol, 44%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.23-1.28?(4H,?m),?1.31-1.40?(2H,?m),?1.44-1.56?(4H,?m),?1.70-1.79?(4H,?m),?1.93-2.08?(4H,?m),?2.32?(3H,?s),?2.82?(1H,?s),?3.79?(3H,?s),?4.57-4.64?(1H,?m),?4.67-4.71?(1H,?m),?6.38?(1H,?s),?6.84?(2H,?d,?J=8.4?Hz),?7.08-7.08?(4H,?m),?7.19?(2H,?J=8.4?Hz).
ESI-MS:?m/z=?505?(M+H)
+。
Synthesize same method according to above-claimed cpd 59 and compound 60, synthesize following compound.
[table 7]
(compound 63)
According to mono succinate-4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl ester of following order synthesis as compound 63.
[changing 52]
In 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-1,4-glycol (compound 3) (250 mg, 0.66 mmol) DMF (3.3 ml) solution in add sodium hydride (63.4 mg, 1.45 mmol), stir 30 minutes.Add succinyl oxide (99 mg, 0.99 mmol), stir 12 hours, in reaction solution, then add 1 M hydrochloric acid and ethyl acetate, be extracted with ethyl acetate.With salt water washing organic layer, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 63 (87.0 mg, 0.18 mmol, 28%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.86-1.88?(2H,?m),?1.96-2.02?(4H,?m),?2.08-2.11?(3H,?m),?2.32?(3H,?s),?2.58-2.64?(4H,?m),?3.81?(3H,?s),?4.82-4.88?(1H,?m),?6.38?(1H,?s),?6.84?(2H,?d,?J=8.0?Hz),?7.09-7.09?(4H,?m),?7.18?(2H,?J=8.0?Hz).
ESI-MS:?m/z=?479?(M+H)
+。
(compound 64)
According to following order synthesis (4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl oxygen base) ethyl carbonate cyclohexyl as compound 64.
[changing 53]
In 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-1,4-glycol (compound 3) (400 mg, 1.05 mmol) ethylene dichloride (5.4 ml) solution in add 1-iodine ethyl carbonate cyclohexyl ester (567 mg, 1.90 mmol), diisopropylethylamine (460 μ l, 2.64 mmol), silver chloride (273 mg, 1.90 mmol), at 80 DEG C, stir placement after 12 hours be cooled to room temperature, reaction solution is passed through diatomite filtration.In filtrate, add 1 M hydrochloric acid and ethyl acetate, be then extracted with ethyl acetate.With salt water washing organic layer, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain compound 64 (31.9 mg, 0.058 mmol, 5.1%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.15-1.34?(9H,?m),?1.48-1.65?(4H,?m),?1.83-1.98?(8H,?m),?2.33?(3H,?s),?2.49?(1H,?s),?3.52-3.58?(1H,?m),?3.64-3.71?(1H,?m),?3.81?(3H,?s),?4.92?(1H,?q,?J=5.2?Hz),?6.39?(1H,?s),?6.84?(2H,?d,?J=8.8?Hz),?7.09-7.09?(4H,?m),?7.19?(2H,?J=8.8?Hz).
ESI-MS:?m/z=?549?(M+H)
+。
According to the method same with the synthesis of above-claimed cpd 59 and compound 60, synthesize following compound.
[table 8]
(compound 67)
According to 2-Padil 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl of following order synthesis as compound 67.
[changing 54]
At room temperature, at 2-benzyloxycarbonyl Padil 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl (intermediate 57) (33.2 mg, 0.058 mmol) methyl alcohol (2.00 mL) solution in add 10% palladium/carbon (6.16 mg, 50%wt), carry out under a hydrogen atmosphere stirring for 14 hours.By reaction solution by diatomite filtration, concentrating under reduced pressure filtrate.By resistates flash column chromatography (NH silica gel, chloroform/methanol) purifying, obtain compound 67 (18.4 mg, 0.042 mmol, 73%) with colourless armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.58-1.82?(2H,?m),?1.88-2.12(9H,?m),?2.33?(3H,?s),?3.43?(2H,?s),?3.81?(3H,?s),?4.88-4.94?(1H,?m),?6.37?(1H,?s),?6.83-6.87?(2H,?m),?7.09-7.11?(4H,?m),?7.18-7.22?(2H,?m).
ESI-MS:?m/z=?436?(M+H)
+。
According to the method same with the synthesis of above-claimed cpd 67, synthesize following compound.
[table 9]
(compound 69)
According to 2-amino-3 Methylbutanoic acid (S)-4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl of following order synthesis as compound 69.
[changing 55]
At room temperature, at 2-(Benzyoxycarbonylamino)-3 Methylbutanoic acid (S)-4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) cyclohexyl oxygen base) methyl esters (intermediate 59) (122 mg, 2 are added in 0.190 mmol) diox/ethanol (2.00 mL/2.00 mL) mixing solutions, 2 '-dipyridyl (15.0 mg, 0.096 mmol), 10% palladium/carbon (49.0 mg, 40%wt), carry out under a hydrogen atmosphere stirring for 14 hours.By reaction solution by diatomite filtration, concentrating under reduced pressure filtrate.By resistates flash column chromatography (silica gel, chloroform/methanol) purifying, obtain compound 69 (38.6 mg, 0.076 mmol, 40%) with colourless armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?0.92?(3H,?d,?J=6.8?Hz),?1.02?(3H,?d,?J=6.8?Hz),?1.90-2.12?(9H,?m),?2.34?(3H,?s),?3.32-3.34?(1H,?m),?3.67-3.76?(1H,?m),?3.81?(3H,?s),?5.41?(1H,?d,?J=6.4?Hz),?5.47?(1H,?d,?J=6.4?Hz),?6.38,?(1H,?s),?6.83-6.87?(2H,?m),?7.09-7.12?(4H,?m),?7.18-7.22?(2H,?m).
ESI-MS:?m/z=?490?(M-OH)
+。
(compound 70)
According to 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl dihydrogen phosphoric acid ester of following order synthesis as compound 70.
[changing 56]
At 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl di(2-ethylhexyl)phosphate benzyl ester (intermediate 60) (251 mg, 0.393 mmol), add 10% palladium/carbon (41.8 mg in the mixing solutions of methyl alcohol (2.6 mL) and ethyl acetate (2.6 mL), 50%wt), under a hydrogen atmosphere, at room temperature stir 2.5 hours.By reaction solution by diatomite filtration, concentrating under reduced pressure filtrate.By resistates recrystallization from methylene dichloride/diethyl ether, obtain compound 70 (97.2 mg, 0.212 mmol, 54%) as a white solid.
1H-NMR?(400?MHz,?DMSO-d
6)?δ:?1.68-1.98?(8H,?m),?2.28?(3H,?s),?3.76?(3H,?s),?4.13?(1H,?br),?4.92?(1H,?br),?6.53?(1H,?s),?6.91-6.95?(2H,?m),?7.08-7.17?(6H,?m).
ESI-MS:?m/z=?459?(M+H)
+。
(intermediate 1)
According to 8-ethynyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 1.
[changing 57]
At-76 DEG C, at trimethylsilyl acetylene (27.1 mL, 2.77 M n-Butyl Lithium (hexane solutions were dripped with 30 minutes in tetrahydrofuran (THF) (300 mL) solution 0.192mol), 69.3 mL, 0.192mol), stir 30 minutes at such a temperature, then 1 was dripped at-74 DEG C with 30 minutes, 4-dioxo spiro [4.5] decane-8-ketone (25.0 g, 0.160 mol) tetrahydrofuran (THF) (100 mL) solution, at such a temperature stir 1 hour 30 minutes.Reaction solution is injected in saturated aqueous ammonium chloride, is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.
In resistates, add methyl alcohol (320 mL), dissolve, add salt of wormwood (55.3 g, 0.400 mol), at room temperature stir 2 hours, concentrating under reduced pressure reaction solution.In resistates, add distilled water, be extracted with ethyl acetate.By organic layer distilled water with use salt water washing.By organic over anhydrous dried over sodium sulfate, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 1 (29.1 g, 0.160mol, 100%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.75-2.03?(9H,?m),?2.49?(1H,?m),?3.95?(4H,?s).
ESI-MS:?m/z=?165?(M-OH)
+。
(intermediate 2)
According to 1-(3-hydroxyl-3-p-methylphenyl propine-1-base) hexalin of following order synthesis as intermediate 2.
[changing 58]
At-78 DEG C, 2.77 M n-Butyl Lithiums (hexane solution, 3.6 mL are dripped in tetrahydrofuran (THF) (20 mL) solution of 1-ethynylcyclohexanol (500 mg, 4.02 mmol), 9.90 mmol), stir 1 hour at such a temperature.At-78 DEG C, in reaction solution, add p-tolualdehyde (0.52 mL, 4.40 mmol), be slowly warming up to room temperature while stirring.In reaction solution, add distilled water and 1 M hydrochloric acid, make acidity, be then extracted with ethyl acetate.By organic over anhydrous dried over mgso, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 2 (598 mg, 2.44 mmol, 61%) with the form of faint yellow solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.18-1.30?(1H,?m),?1.47-1.74?(7H,?m),?1.89-1.98?(2H,?m),?2.08?(1H,?brs),?2.22?(1H,?brs),?2.36?(3H,?s),?5.47?(1H,?s),?7.19?(2H,?d,?J=8.0?Hz),?7.43?(2H,?d,?J=8.0?Hz).
ESI-MS:?m/z=?227?(M-OH)
+。
(intermediate 3)
According to 8-(3-hydroxyl-3-p-methylphenyl propine-1-base)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 3.
[changing 59]
At-72 DEG C, at 8-ethynyl-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 1) (15.0 g, 82.3 mmol) tetrahydrofuran (THF) (165 mL) solution in 25 minutes drip 2.77 M n-Butyl Lithium (hexane solutions, 62.4 mL, 172.9 mmol), stir 30 minutes at such a temperature, then at-72 DEG C, 5 minutes p-tolualdehyde (10.2 mL are dripped, 86.4 mmol), stir 30 minutes at such a temperature.Reaction solution is warming up to room temperature, is then injected in saturated aqueous ammonium chloride.Reaction solution is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 3 (17.7 g, 58.5 mmol, 71%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.72-1.85?(4H,?m),?1.90-2.04?(4H,?m),?2.35?(3H,?s),?2.55?(1H,?s),?2.78?(1H,?d,?J=6.0?Hz),?3.93?(4H,?s),?5.44?(1H,?d,?J=6.0?Hz),?7.17?(2H,?d,?J=8.0?Hz),?7.40?(2H,?d,?J=8.0?Hz).
ESI-MS:?m/z=?285?(M-OH)
+。
(intermediate 4)
According to 8-(3-hydroxyl-3-(4-p-methoxy-phenyl) propine-1-base)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 4.
[changing 60]
At-72 DEG C, at 8-ethynyl-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 1) (5.02 g, 27.6 mmol) tetrahydrofuran (THF) (100 mL) solution in 15 minutes drip 2.63 M n-Butyl Lithium (hexane solutions, 22.0 mL, 57.9 mmol), stir 60 minutes at such a temperature, then at-72 DEG C, 4-methoxyl group formaldehyde (3.52 mL were dripped with 10 minutes, 28.9 mmol), stir 60 minutes at such a temperature.Reaction solution is warming up to room temperature, is then injected in saturated aqueous ammonium chloride.Reaction solution is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 4 (7.46 g, 23.4 mmol, 85%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.73-1.85?(4H,?m),?1.91-2.04?(4H,?m),?2.32?(1H,?s),?2.52?(1H,?d,?J=6.1?Hz),?3.81?(3H,?s),?3.94?(4H,?s),?5.44?(1H,?d,?J=6.1?Hz),?6.89?(2H,?d,?J=8.5?Hz),?7.44?(2H,?d,?J=8.5?Hz)。
(intermediate 5)
According to 8-(3-(4-chloro-phenyl-)-3-hydroxypropyn-1-base)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 5.
[changing 61]
At-72 DEG C, at 8-ethynyl-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 1) (5.03 g, 27.6 mmol) tetrahydrofuran (THF) (100 mL) solution in 15 minutes drip 2.63 M n-Butyl Lithium (hexane solutions, 22.1 mL, 57.9 mmol), stir 60 minutes at such a temperature, then at-72 DEG C, 4-chlorobenzaldehyde (4.06 g were dripped with 10 minutes, 28.9 mmol), stir 60 minutes at such a temperature.Reaction solution is warming up to room temperature, is then injected in saturated aqueous ammonium chloride.Reaction solution is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 5 (8.13 g, 25.2 mmol, 91%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.68-1.81?(4H,?m),?1.86-1.90?(4H,?m),?3.55?(1H,?s),?3.90?(4H,?s),?4.03?(1H,?d,?J=4.2?Hz),?5.41?(1H,?d,?J=4.2?Hz),?7.28?(2H,?d,?J=8.3?Hz),?7.41?(2H,?d,?J=8.3?Hz)。
According to the method same with the synthesis of above-mentioned intermediate 1-5, synthesize following compound.
[table 10]
(intermediate 8)
According to 3-(1-the hydroxy-cyclohexyl)-1-p-methylphenyl-2-propine-1-ketone of following order synthesis as intermediate 8.
[changing 62]
Manganse Dioxide (1.15 g are added in methylene dichloride (20 mL) solution of 1-(3-hydroxyl-3-p-methylphenyl propine-1-base) hexalin (intermediate 2) (593 mg, 2.42 mmol), 13.2 mmol), at room temperature stir 5 hours.By diatomite filtration reaction solution, concentrating under reduced pressure filtrate.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 8 (534 mg, 2.20 mmol, 91%) with the form of pale yellow oil.
1H-NMR?(400?MHz,?CDCl
3)?δ:1.28-1.39?(1H,?m),?1.55-1.84?(7H,?m),?2.02-2.11?(2H,?m),?2.23?(1H,?brs),?2.43?(3H,?s),?7.28?(2H,?d,?J=8.0?Hz),?8.02?(2H,?d,?J=8.0?Hz)。
(intermediate 9)
According to 3-(8-hydroxyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-the base)-1-p-methylphenyl-2-propine-1-ketone of following order synthesis as intermediate 9.
[changing 63]
At 8-(3-hydroxyl-3-p-methylphenyl propine-1-base)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 3) (17.5 g, 57.9 mmol) methylene dichloride (289 mL) solution in add Manganse Dioxide (29.6 g, 289 mmol), at room temperature carry out stirring for 15 hours.By diatomite filtration reaction solution, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 9 (14.3 g, 47.6 mmol, 82%) with the form of oily mater.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.79-1.85?(2H,?m),?1.87-1.93?(2H,?m),?2.04-2.15?(4H,?m),?2.20?(1H,?s),?2.43?(3H,?s),?3.97?(4H,?s),?7.28?(2H,?d,?J=8.0?Hz),?8.00?(2H,?d,?J=8.0?Hz).
ESI-MS:?m/z=?284?(M-OH)
+。
(intermediate 10)
According to 3-(8-hydroxyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-base)-1-(6-picoline-3-the base)-2-propine-1-ketone of following order synthesis as intermediate 10.
[changing 64]
At-78 DEG C, at 8-ethynyl-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 1) (592 mg, 3.25 mmol) tetrahydrofuran (THF) (6 mL) solution in 5 minutes drip 2.63 M n-Butyl Lithium (hexane solutions, 2.6 mL, 6.82 mmol), stir 30 minutes at such a temperature, then at-78 DEG C, N-methoxy-. N-methyl-6-methylnicotinamide (614.5 mg were dripped with 20 minutes, 3.41 mmol) tetrahydrofuran (THF) (5 ml) solution, at such a temperature stir 30 minutes.Reaction solution is warming up to room temperature, is then injected in saturated aqueous ammonium chloride.Reaction solution is extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 10 (626.3 mg, 2.08 mmol, 65%) with the form of faint yellow solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.76-1.83?(2H,?m),?1.87-1.94?(2H,?m),?2.04-2.10?(2H,?m),?2.12-2.19?(2H,?m),?2.30?(1H,?s),?2.66?(3H,?s),?3.97?(4H,?s),?7.29?(1H,?d,?J=8.0?Hz),?8.22?(1H,?dd,?J=2.4,?8.0?Hz),?9.21?(1H,?d,?J=2.4?Hz).
ESI-MS:?m/z=?284?(M-OH)
+。
(intermediate 11)
According to 3-(8-hydroxyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-base)-1-(4-the p-methoxy-phenyl)-2-propine-1-ketone of following order synthesis as intermediate 11.
[changing 65]
At 8-(3-hydroxyl-3-(4-p-methoxy-phenyl) propine-1-base)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 4) (7.10 g, 22.3 mmol) methylene dichloride (100 mL) solution in add Manganse Dioxide (9.69 g, 112 mmol), at room temperature carry out stirring for 18 hours.By diatomite filtration reaction solution, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 11 (5.45 g, 17.2 mmol, 77%) with the form of oily mater.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.78-1.93?(4H,?m),?2.03-2.17?(4H,?m),?2.27?(1H,?s),?3.89?(3H,?s),?3.97?(4H,?s),?6.95?(2H,?d,?J=9.0?Hz),?8.08?(2H,?d,?J=9.0?Hz).
ESI-MS:?m/z=?299?(M-OH)
+。
(intermediate 12)
According to 1-(4-chloro-phenyl-)-3-(8-hydroxyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-the base)-2-propine-1-ketone of following order synthesis as intermediate 12.
[changing 66]
At 8-(3-(4-chloro-phenyl-)-3-hydroxypropyn-1-base)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 5) (7.70 g, 23.9 mmol) methylene dichloride (120 mL) solution in add Manganse Dioxide (10.4 g, 119 mmol), at room temperature carry out stirring for 18 hours.By diatomite filtration reaction solution, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 12 (5.45 g, 17.0 mmol, 71%) with the form of oily mater.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.77-1.94?(4H,?m),?2.04-2.19?(4H,?m),?2.15?(1H,?s),?3.98?(4H,?s),?7.47?(2H,?d,?J=8.5?Hz),?8.04?(2H,?d,?J=8.5?Hz).
ESI-MS:?m/z=?303?(M-OH)
+。
According to the method same with the synthesis of above-mentioned intermediate 8-12, synthesize following compound.
[table 11]
(intermediate 18)
According to 8-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 18.
[changing 67]
In ethanol (76.6 mL) solution of 4-p-methoxy-phenyl hydrazine hydrochloride (7.35 g, 42.1 mmol), drip triethylamine (5.87 mL, 42.1 mmol), at room temperature carry out stirring for 30 minutes.3-(8-hydroxyl-1 is dripped in reaction solution, 4-dioxo spiro [4.5] decane-8-base)-1-p-methylphenyl-2-propine-1-ketone (intermediate 9) (11.5 g, 38.3 mmol) ethanol (76.6 mL) solution, at room temperature carry out stirring for 15 hours, then concentrating under reduced pressure reaction solution.In resistates, add water, be extracted with ethyl acetate.By organic layer 1 M hydrochloric acid, distilled water and salt water washing, then use anhydrous magnesium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 18 (14.7 g, 35.0 mmol, 91%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.71-1.74?(2H,?m),?1.99-2.25?(6H,?m),?2.33?(3H,?s),?2.71?(1H,?s),?3.81?(3H,?s),?3.96-4.01?(4H,?m),?6.39?(1H,?s),?6.84?(2H,?d,?J=8.0?Hz),?7.09?(4H,?s),?7.21?(2H,?d,?J=8.0?Hz).
ESI-MS:?m/z=?421?(M+H)
+。
(intermediate 19)
According to 8-(1-(4-p-methoxy-phenyl)-5-(6-picoline-3-base)-1H-pyrazole-3-yl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 19.
[changing 68]
In ethanol (4 mL) solution of 4-p-methoxy-phenyl hydrazine hydrochloride (359 mg, 2.06 mmol), drip triethylamine (286 μ L, 2.06 mmol), at room temperature carry out stirring for 30 minutes.3-(8-hydroxyl-1 is dripped in reaction solution, 4-dioxo spiro [4.5] decane-8-base)-1-(6-picoline-3-base)-2-propine-1-ketone (intermediate 10) (563.7 mg, 1.87 mmol) ethanol (5.4 mL) solution, at room temperature carry out stirring for 22 hours, then concentrating under reduced pressure reaction solution.In resistates, add water, be extracted with ethyl acetate.By organic layer distilled water and salt water washing, then use anhydrous magnesium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 19 (177 mg, 0.42 mmol, 22%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.72-1.75?(2H,?m),?2.00-2.03?(2H,?m),?2.07-2.14?(2H,?m),?2.19-2.26?(2H,?m),?2.55?(3H,?s),?2.65?(1H,?s),?3.81?(3H,?s),?3.96-4.03?(4H,?m),?6.47?(1H,?s),?6.86?(2H,?d,?J=8.8?Hz),?7.06?(1H,?d,?J=8.0?Hz),?7.20?(2H,?d,?J=8.8?Hz),?7.33?(1H,?dd,?J=2.2,?8.0?Hz),?8.40?(1H,?d,?J=2.2?Hz).
ESI-MS:?m/z=?422?(M+H)
+。
(intermediate 20)
According to 8-(1,5-two (4-p-methoxy-phenyl)-1H-pyrazole-3-yl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 20.
[changing 69]
At 3-(8-hydroxyl-1,4-dioxo spiro [4.5] decane-8-base)-1-(4-p-methoxy-phenyl)-2-propine-1-ketone (intermediate 11) (700 mg, 2.24 mmol) ethanol (4.5 mL) solution in add 4-p-methoxy-phenyl hydrazine hydrochloride (470 mg, 2.69 mmol), triethylamine (0.74 mL, 5.41 mmol) ethanol (4.5 mL) solution, at room temperature stir 20 hours.Concentrating under reduced pressure reaction solution, adds distilled water in resistates, is extracted with ethyl acetate.Use anhydrous magnesium sulfate drying organic layer, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 20 (864 mg, 1.98 mmol, 88%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.68-1.77?(2H,?m),?1.96-2.26?(6H,?m),?2.70?(1H,?brs),?3.80?(3H,?s),?3.81?(3H,?s),?3.94-4.04?(4H,?m),?6.37(1H,?s),?6.81?(2H,?d,?J=8.8?Hz),?6.85?(2H,?d,?J=8.8?Hz),?7.13?(2H,?d,?J=8.8?Hz),?7.21?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?437?(M+H)
+。
(intermediate 21)
According to 8-(5-(4-chloro-phenyl-)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 21.
[changing 70]
In ethanol (4.4 mL) solution of 4-p-methoxy-phenyl hydrazine hydrochloride (457 mg, 2.62 mmol), drip triethylamine (0.730 mL, 5.24 mmol), at room temperature carry out stirring for 30 minutes.1-(4-chloro-phenyl-)-3-(8-hydroxyl-1 is dripped in reaction solution, 4-dioxo spiro [4.5] decane-8-base)-2-propine-1-ketone (intermediate 12) (700 mg, 2.18 mmol) ethanol (4.4 mL) solution, at room temperature carry out stirring for 14 hours, then concentrating under reduced pressure reaction solution.In resistates, add water, be extracted with ethyl acetate.By organic layer 1 M hydrochloric acid, distilled water and salt water washing, then use anhydrous magnesium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 21 (756 mg, 1.71 mmol, 79%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.69-1.76?(2H,?m),?1.97-2.25?(6H,?m),?2.66?(1H,?brs),?3.82?(3H,?s),?3.94-4.03?(4H,?m),?6.43?(1H,?s),?6.85-6.87?(2H,?m),?7.13?(2H,?d,?J=8.4?Hz),?7.19?(2H,?d,?J=8.4?Hz),?7.25-7.27?(2H,?m).
ESI-MS:?m/z=?441?(M+H)
+。
(intermediate 22)
According to 8-(1-(4-chloro-phenyl-)-5-p-methylphenyl-1H-pyrazole-3-yl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 22.
[changing 71]
In ethanol (4.8 mL) solution of 4-chloro-phenyl-hydrazine hydrochloride (418 mg, 2.33 mmol), drip triethylamine (5.87 mL, 42.1 mmol), at room temperature carry out stirring for 30 minutes.3-(8-hydroxyl-1 is dripped in reaction solution, 4-dioxo spiro [4.5] decane-8-base)-1-p-methylphenyl-2-propine-1-ketone (intermediate 9) (698 mg, 2.32 mmol) ethanol (4.7 mL) solution, at room temperature carry out stirring for 14 hours, then concentrating under reduced pressure reaction solution.In resistates, add water, be extracted with ethyl acetate.By organic layer distilled water and salt water washing, then use anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 22 (948 mg, 2.23 mmol, yield 96%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.71-1.75?(2H,?m),?1.98-2.14?(4H,?m),?2.17-2.25?(2H,m),?2.36?(3H,?s),?2.62?(1H,?s),?3.96-4.03?(4H,?m),?6.41?(1H,?s),?7.09?(2H,?d,?J=8.0?Hz),?7.13?(2H,?d,?J=8.0?Hz),?7.22-7.30?(4H,?m).
ESI-MS:?m/z=?407?(M-OH)
+。
Following compound is synthesized according to the method same with above-mentioned intermediate 18-22.
[table 12-1]
[table 12-2]
[table 12-3]
[table 12-4]
(intermediate 38)
According to oxalic acid 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-cis-Isosorbide-5-Nitrae-two base ester of following order synthesis as intermediate 38.
[changing 72]
In 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-1,4-glycol (compound 3) (300 mg, 0.793 mmol) methylene dichloride (2.6 mL) suspension in add diacetyl oxide (0.187 mL, 1.98 mmol), pyridine (0.192 mL, 2.38 mmol), 4-dimethylaminopyridine (48.4 mg, 0.396 mmol), at room temperature stir 60 hours.Add 4-dimethylaminopyridine (48.4 mg, 0.396 mmol) again, at room temperature stir 6 hours further.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 38 (297 mg, 0.642 mmol, 81%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.74-1.82?(2H,?m),?1.92-1.98?(2H,?m),?2.01-2.08?(5H,?m),?2.10?(3H,?s),?2.32?(3H,?s),?2.70-2.77?(2H,?m),?3.80?(3H,?s),?4.80-4.89?(1H,?m),?6.38?(1H,?s),?6.83?(2H,?d,?J=8.8?Hz),?7.08?(4H,?s),?7.20?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?463?(M+H)
+。
(intermediate 39)
According to acetic acid c-4-methoxyl group-1-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester of following order synthesis as intermediate 39.
[changing 73]
Under ice-cooled stirring, at acetic acid c-4-hydroxyl-1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester (intermediate 84) (0.150 g, 0.357 mmol) N, 55% sodium hydride (23.4 mg are added in dinethylformamide (1.8 mL) solution, 0.535 mmol) and methyl-iodide (29.0 μ L, 0.464 mmol), at room temperature stir 9 hours.Under ice-cooled stirring, in reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 39 (124 mg, 0.284 mmol, 80%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.60-1.68?(2H,?m),?1.94-2.03?(4H,?m),?2.08?(3H,?s),?2.32?(3H,?s),?2.69-2.76?(2H,?m),?3.24-3.33?(1H,?m),?3.39?(3H,?s),?3.80?(3H,?s),?6.37?(1H,?s),?6.83?(2H,?d,?J=8.8?Hz),?7.08?(4H,?s),?7.20?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?435?(M+H)
+。
(intermediate 40)
According to acetic acid 4-(4-fluoro-1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-the pyrazole-3-yl)-c-4-hydroxy-cyclohexan alkane-r-1-base ester of following order synthesis as intermediate 40.
[changing 74]
Selectfluor is added in acetonitrile (3.09 mL) solution of acetic acid c-4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester (compound 12) (130 mg, 0.309 mmol)
tM(120 mg, 0.340 mmol), at room temperature stirs 3 hours.In reaction solution, add saturated aqueous sodium thiosulfate, be extracted with ethyl acetate.By organic layer washed with brine, then use anhydrous magnesium sulfate drying, concentrating under reduced pressure, by resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 40 (61 mg with faint yellow armorphous form, 0.140 mmol, 45%).
1H-NMR?(400MHz,?CDCl
3)δ:?1.89-2.15?(11H,?m),?2.35?(3H,?m),?2.73?(1H,?s),?3.81?(3H,?s),?4.82-4.89?(1H,?m),?6.84-6.86?(2H,?m),?7.10-7.18?(6H,?m).
ESI-MS:?m/z=?439?(M+H)
+。
(intermediate 41)
According to acetic acid 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-the pyrazole-3-yl)-4-oxo-cyclohexyl-1-base ester of following order synthesis as intermediate 41.
[changing 75]
At acetic acid c-4-hydroxyl-1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester (intermediate 84) (142 mg, 0.338 mmol) methylene dichloride (3.38 mL) solution in add Dai Si-Martin reagent (172 mg, 0.405 mmol), stir 2 hours at 0 DEG C.Reaction solution is carried out diatomite filtration, by resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtains intermediate 41 (120 mg, 0.287 mmol, 85%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.13?(3H,?s),?2.33?(3H,?s),?2.44-2.52?(4H,?m),?2.59-2.65?(2H,?m),?2.93-2.96?(2H,?m),?3.81?(3H,?s),?6.45?(1H,?s),?6.84?(2H,?d,?J=8.8?Hz),?7.08?(4H,?s),?7.20?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?419?(M+H)
+。
(intermediate 42)
According to c-4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-hexanaphthene-r-1-formaldehyde of following order synthesis as intermediate 42.
[changing 76]
At-40 DEG C, at (methoxymethyl) triphenyl phosphonium chloride (546.3 mg, 1.59 mmol) tetrahydrofuran (THF) (1.3 mL) solution in add potassium tert.-butoxide (178.7 mg, 1.59 mmol), at such a temperature stir 60 minutes.At-40 DEG C, 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-1-ketone (compound 4) (200 mg are dripped in reaction solution, 0.53 mmol) tetrahydrofuran (THF) (1.35 mL) solution, then at room temperature stir 1.5 hours.At 0 DEG C, in reaction solution, add 6 M aqueous hydrochloric acids, stir 12 hours.In reaction solution, add distilled water, be extracted with ethyl acetate.By organic layer saturated sodium bicarbonate aqueous solution, salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure, by resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, intermediate 42 (87.5 mg, 0.23 mmol, 42%) is obtained with the form of colourless oily mater.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.88-1.96?(6H,?m),?2.09-2.11?(2H,?m),?2.25-2.36?(5H,?m),?3.80?(3H,?s),?6.39?(1H,?s),?6.84?(2H,?d,?J=8.8?Hz),?7.09-7.14?(4H,?m),?7.20?(2H,?d,?J=8.8?Hz),?9.66?(1H,?d,?J=2.0?Hz).
ESI-MS:?m/z=?391?(M+H)
+。
(intermediate 43)
According to Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-ethyl formate of following order synthesis as intermediate 43.
[changing 77]
At 4-oxocyclohex alkane ethyl formate (10.0 g, 58.8 mmol) toluene (196 mL) solution in add ethylene glycol (3.6 mL, 64.6 mmol) and tosic acid monohydrate (1.12 g, 5.88 mmol), reflux at 150 DEG C.Stir 18 hours.In reaction solution, add saturated sodium bicarbonate water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 43 (12.3 g, 57.4 mmol, 98%) with the form of colorless oil compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.25?(3H,?t,?J=7.2?Hz),?1.51-1.61?(2H,?m),?1.75-1.86?(4H,?m),?1.90-1.98?(2H,?m),?2.29-2.38?(1H,?s),?3.95?(4H,?s),?4.13?(2H,?q,?J=7.2?Hz).
ESI-MS:?m/z=?215?(M+H)
+。
(intermediate 44)
According to 8-(benzyloxymetliyl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-ethyl formate of following order synthesis as intermediate 44.
[changing 78]
At-78 DEG C, 1,4-dioxo spiro [4.5] decane-8-ethyl formate (intermediate 43) (500 mg, 2.33 mmol) tetrahydrofuran (THF) (7.8 mL) solution in add two (trimethyl silyl) amido potassium (toluene solution of 0.5 M, 4.67 mL, 2.33 mmol), stir 20 minutes, then Benzyl chloromethyl ether (0.379 mL is added, 2.45 mmol), stir 30 minutes at-78 DEG C, at room temperature stir 1.5 hours.In reaction solution, add saturated aqueous ammonium chloride, be extracted with ethyl acetate.By organic over anhydrous dried over sodium sulfate, concentrating under reduced pressure.In resistates, add 3 M aqueous sodium hydroxide solutions (1.0 mL), stir 4 hours.Reaction solution ether is extracted, with salt water washing organic layer, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 44 (279 mg, 0.834 mmol, 36%) with the form of colorless oil compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.24?(3H,?t,?J=7.2?Hz),?1.52-1.68?(6H,?m),?2.16-2.23?(2H,?m),?3.46?(2H,?s),?3.88-3.96?(4H,?m),?4.17?(2H,?q,?J=7.2?Hz),?4.49?(2H,?s),?7.25-7.39?(5H,?m).
ESI-MS:?m/z=?335?(M+H)
+。
(intermediate 45)
According to following order synthesis (8-(benzyloxymetliyl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-base) methyl alcohol as intermediate 45.
[changing 79]
Under ice-cooled stirring, at 8-(benzyloxymetliyl)-1,4-dioxo spiro [4.5] decane-8-ethyl formate (intermediate 44) (279 mg, 0.834 mmol) tetrahydrofuran (THF) (4.2 mL) solution in add lithium borohydride (91.0 mg, 4.17 mmol), stir 4 hours at 70 DEG C.In reaction solution, add saturated aqueous ammonium chloride, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 45 (183 mg, 0.625 mmol, 75%) with the form of colorless oil compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.48-1.66?(8H,?m),?2.76?(1H,?t,?J=6.0?Hz),?3.43?(2H,?s),?3.60?(2H,?d,?J=6.0?Hz),?3.91-3.95?(4H,?m),?4.52?(2H,?s),?7.27-7.38?(5H,?m).
ESI-MS:?m/z=?293?(M+H)
+。
(intermediate 46)
According to 8-(benzyloxymetliyl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-formaldehyde of following order synthesis as intermediate 46.
[changing 80]
At (8-(benzyloxymetliyl)-1,4-dioxo spiro [4.5] decane-8-base) methyl alcohol (intermediate 45) (183 mg, 0.625 mmol) DMSO (2.1 mL) solution in add 50% sulfur trioxide-pyridine complex compound (596 mg, 1.87 mmol) and triethylamine (0.522 mL, 3.75 mmol), at room temperature stir 20 minutes.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.Organic layer is used successively 20% aqueous citric acid solution, saturated sodium bicarbonate water, salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 46 (172 mg, 0.592 mmol, 95%) with the form of colorless oil compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.55-1.67?(6H,?m),?2.03-2.11?(2H,?m),?3.45?(2H,?s),?3.90-3.95?(4H,?m),?4.47?(2H,?s),?7.25-7.36?(5H,?m),?9.60?(1H,?s).
ESI-MS:?m/z=?291?(M+H)
+。
(intermediate 47)
According to 8-(benzyloxymetliyl)-8-ethynyl-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane of following order synthesis as intermediate 47.
[changing 81]
Under ice-cooled stirring, at 8-(benzyloxymetliyl)-1,4-dioxo spiro [4.5] decane-8-formaldehyde (intermediate 46) (100 mg, 0.344 mmol) methyl alcohol (5.2 mL) solution in add salt of wormwood (143 mg, 1.03 mmol) and 1-diazo-2-oxopropyl dimethyl phosphonate (165 mg, 0.861 mmol), at room temperature stir 1 hour.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 47 (88.9 mg, 0.310 mmol, 90%) with the form of colorless oil compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.52-1.71?(4H,?m),?1.77-1.85?(2H,?m),?1.94-2.04?(2H,?m),?2.19?(1H,?s),?3.38?(2H,?s),?3.89-3.99?(4H,?s),?4.61?(2H,?s),?7.25-7.37?(5H,?m).
ESI-MS:?m/z=?287?(M+H)
+。
(intermediate 48)
According to 3-(8-(benzyloxymetliyl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-the base)-1-p-methylphenyl propine-1-alcohol of following order synthesis as intermediate 48.
[changing 82]
At-78 DEG C, at 8-(benzyloxymetliyl)-8-ethynyl-1,4-dioxo spiro [4.5] decane (intermediate 47) (393 mg, 1.37 mmol) tetrahydrofuran (THF) (4.6 mL) solution in add 2.6 M n-Butyl Lithium (hexane solutions, 0.555 mL, 1.44 mmol), stir 10 minutes.Add 4-tolyl aldehyde (0.178 mL, 1.51 mmol) further, be then slowly warming up to room temperature, stir 1 hour.In reaction solution, add saturated aqueous ammonium chloride, be extracted with ethyl acetate.With salt water washing organic layer, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 48 (459 mg, 1.13 mmol, 82%) with the form of colorless oil compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.62-1.71?(4H,?m),?1.79-1.86?(2H,?m),?1.92-2.02?(2H,?m),?2.23?(1H,?brs),?2.34?(3H,?s),?3.41?(2H,?s),?3.89-3.98?(4H,?m),?4.59?(2H,?m),?5.44?(1H,?d,?J=5.2?Hz),?7.15?(2H,?d,?J=8.0?Hz),?7.25-7.35?(5H,?m),?7.43?(2H,?d,?J=8.0?Hz).
ESI-MS:?m/z=?407?(M+H)
+。
(intermediate 49)
According to 3-(8-(benzyloxymetliyl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-the base)-1-p-methylphenyl propine-1-ketone of following order synthesis as intermediate 49.
[changing 83]
At 3-(8-(benzyloxymetliyl)-1,4-dioxo spiro [4.5] decane-8-base)-1-p-methylphenyl propine-1-alcohol (intermediate 48) (585 mg, 1.44 mmol) methylene dichloride (7.2 mL) solution in add Manganse Dioxide (625 mg, 7.19 mmol), at room temperature stir 13 hours.By reaction solution diatomite filtration, then concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 49 (540 mg, 1.33 mmol, 93%) with the form of colorless oil compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.71-1.80?(4H,?m),?1.97-2.03?(4H,?m),?2.41?(3H,?s),?3.52?(2H,?s),?3.91-4.00?(4H,?m),?4.63?(2H,?m),?7.21?(2H,?d,?J=8.0?Hz),?7.25-7.38?(5H,?m),?8.03?(2H,?d,?J=8.0?Hz).
ESI-MS:?m/z=?405?(M+H)
+。
(intermediate 50)
According to 3-(8-(benzyloxymetliyl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-base)-1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazoles of following order synthesis as intermediate 50.
[changing 84]
In ethanol (2.7 mL) solution of 4-p-methoxy-phenyl hydrazine hydrochloride (280 mg, 1.60 mmol), drip triethylamine (0.447 mL, 3.20 mmol), at room temperature carry out stirring for 30 minutes.3-(8-(benzyloxymetliyl)-1 is dripped in reaction solution, 4-dioxo spiro [4.5] decane-8-base)-1-p-methylphenyl propine-1-ketone (intermediate 49) (540 mg, 1.33 mmol) ethanol (2.7 mL) solution, at room temperature carry out stirring for 14 hours, then concentrating under reduced pressure reaction solution.In resistates, add water, be extracted with ethyl acetate.By organic layer 1 M hydrochloric acid, distilled water and salt water washing, then use anhydrous magnesium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 50 (458 mg, 0.872 mmol, 65%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.64-1.72?(2H,?m),?1.76-1.85?(2H,?m),?1.89-1.98?(2H,?m),?2.27-2.35?(5H,?m),?3.50?(2H,?s),?3.80?(3H,?s),?3.90-3.99?(4H,?m),?4.49?(2H,?s),?6.38?(1H,?s),?6.80-6.85?(2H,?m),?7.06-7.31?(11H,?m).
ESI-MS:?m/z=?525?(M+H)
+。
(intermediate 51)
According to 4-(benzyloxymetliyl)-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-1-ketone of following order synthesis as intermediate 51.
[changing 85]
At 3-(8-(benzyloxymetliyl)-1,4-dioxo spiro [4.5] decane-8-base)-1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazoles (intermediate 50) (458 mg, 0.872 mmol) tetrahydrofuran (THF) (2.2 mL) solution in add 6 M hydrochloric acid (4.4 mL), at room temperature stir 15 hours.Reaction solution is ice-cooled, at 0 DEG C, drip 50% aqueous sodium hydroxide solution, until be alkalescence, be then extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 51 (387 mg, 0.804 mmol, 92%) with the form that white is armorphous.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.11-2.21?(2H,?m),?2.31-2.39?(5H,?m),?2.52-2.68?(4H,?m),?3.57?(2H,?s),?3.81?(3H,?s),?4.51?(2H,?s),?6.44?(1H,?s),?6.83-6.88?(2H,?m),?7.08-7.34?(11H,?m).
ESI-MS:?m/z=?481?(M+H)
+。
(intermediate 52)
According to 8-(4,5-two (4-p-methoxy-phenyl) oxazole)-2-base)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 52.
[changing 86]
At 0 DEG C, at the 2-chloro-1 synthesized according to known manufacture method (No. 07/111323rd, International Publication), two (4-p-methoxy-phenyl) oxazole (1.01 g of 4-, 3.20 mmol) tetrahydrofuran (THF) (32 mL) solution in add 1.09 M borine tetrahydrofuran complex (4.0 mL, 4.36 mmol), stir 1 hour at such a temperature.At-78 DEG C, in reaction solution, add 2.66 M n-Butyl Lithiums (1.47 mL, mmol), stir 1 hour at such a temperature.In reaction solution, add Isosorbide-5-Nitrae-cyclohexanedione monoethylene glycol ketal (524 mg, 3.36 mmol), be slowly warming up to room temperature while stirring.In reaction solution, add 1 M hydrochloric acid, make acidity, be extracted with ethyl acetate.Use anhydrous magnesium sulfate drying organic layer, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 52 (844 mg, 1.92 mmol, 60%) with faint yellow armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.71-1.80?(2H,?m),?2.01-2.11?(4H,?m),?2.30-2.41?(2H,?m),?2.76?(1H,?s),?3.83?(3H,?s),?3.84?(3H,?s),?3.99?(4H,?dd,?J=Hz),?6.89?(2H,?d,?J=8.8?Hz),?6.90?(2H,?d,?J=8.8?Hz),?7.50?(2H,?d,?J=8.8?Hz),?7.56?(2H,?d,?J=8.8?Hz)。
(intermediate 53)
According to Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-methane amide of following order synthesis as intermediate 53.
[changing 87]
At 0 DEG C, triethylamine (5.87 mL are added in tetrahydrofuran (THF) (22 mL) solution of Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-formic acid (823 mg, 4.42 mmol), 42.1 mmol) and n-propyl chloroformate, stir 1 hour at such a temperature.Drip, at room temperature carry out stirring for 30 minutes.In reaction solution, add 28% ammoniacal liquor (1.5 mL), at room temperature stir 1 hour.Separatory organic layer from reaction solution, by dried over sodium sulfate, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 53 (694 mg, 3.75 mmol, 85%) with colourless armorphous form.
1H-NMR?(400?MHz,?CDCl
3)δ:?1.53-1.61?(2H,?m),?1.72-1.86?(4H,?m),?1.91-1.98?(2H,?m),?2.17-2.25?(1H,?m),?3.95?(4H,?s),?5.29?(1H,?brs),?5.46?(1H,?brs).
ESI-MS:?m/z=?186?(M+H)
+。
(intermediate 54)
According to Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-thioformamide of following order synthesis as intermediate 54.
[changing 88]
1,4-dioxo spiro [4.5] decane-8-methane amide (intermediate 53) (281 mg, 1.52 mmol) toluene (5 mL) solution in add lawesson reagent (337 mg, 0.834 mmol), stir 1 hour at 100 DEG C, be cooled to room temperature.In reaction solution, add methyl alcohol, concentrating under reduced pressure, by resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 54 (147 mg, 0.730 mmol, 48%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)δ:?1.57-1.66?(2H,?m),?1.79-1.90?(4H,?m),?1.97-2.03?(2H,?m),?2.64-2.72?(1H,?m),?3.96?(4H,?s),?6.89?(1H,?brs),?7.46?(1H,?brs).
ESI-MS:?m/z=?202?(M+H)
+。
(intermediate 55)
According to 8-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane of following order synthesis as intermediate 55.
[changing 89]
At room temperature, by 1,4-dioxo spiro [4.5] decane-8-thioformamide (intermediate 54) (389 mg, 1.93 mmol) and acetonitrile (9.2 mL) solution stirring 4 hours of the bromo-1-of 2-(4-p-methoxy-phenyl)-2-p-methylphenyl ethyl ketone (588 mg, 1.84 mmol).In reaction solution, add saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 55 (630 mg, 1.49 mmol, 81%) with colourless armorphous form.
1H-NMR?(400?MHz,?CDCl
3)δ:?1.68-1.76?(2H,?m),?1.88-1.98?(4H,?m),?2.18-2.24?(2H,?m),?2.35?(3H,?s),?3.05-3.13?(1H,?m),?3.80?(3H,?s),?3.99?(4H,?s),?6.79-6.82?(2H,?m),?7.11?(2H,?d,?J=8.0?Hz),?7.22?(2H,?d,?J=8.0?Hz),?7.43-7.46?(2H,?m).
ESI-MS:?m/z=?422?(M+H)
+。
(intermediate 56)
According to 8-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl)-Isosorbide-5-Nitrae-dioxo spiro [4.5] decane-8-alcohol of following order synthesis as intermediate 56.
[changing 90]
At-78 DEG C, at 8-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl)-1, add 1.63 M n-Butyl Lithium/hexane solutions (1.17 mL) in tetrahydrofuran (THF) (8.7 mL) solution of 4-dioxo spiro [4.5] decane (intermediate 55) (734 mg, 1.74 mmol), stir 1 hour at such a temperature.At-78 DEG C, reaction solution is joined in tetrahydrofuran (THF) (8.7 mL) solution of 3-phenyl-2-(phenyl sulfonyl)-1,2-oxaziridine (546 mg, 2.09 mmol), be slowly warming up to room temperature while stirring.In reaction solution, add distilled water, be extracted with ethyl acetate.By organic layer washed with brine, then use dried over sodium sulfate, concentrating under reduced pressure, by resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 56 (417 mg with colourless armorphous form, 0.954 mmol, 55%).
1H-NMR?(400?MHz,?CDCl
3)δ:?1.73-1.79?(2H,?m),?2.03-2.10?(4H,?m),?2.32-2.39?(2H,?m),?2.37?(3H,?s),?2.78?(1H,?s),?3.84?(3H,?s),?3.97-4.02?(4H,?m),?6.88-6.92?(2H,?m),?7.16?(2H,?d,?J=8.4?Hz),?7.47?(2H,?d,?J=8.4?Hz),?7.55-7.58?(2H,?m).
ESI-MS:?m/z=?438?(M+H)
+。
(intermediate 57)
According to 2-Benzyoxycarbonylamino acetic acid 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl ester of following order synthesis as intermediate 57.
[changing 91]
At room temperature, in 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-cis-1, 4-glycol (compound 3) (76.0 mg, 0.201 mmol) methylene dichloride (2.00 mL) solution in add triethylamine (0.084 mL, 0.60 mmol), 2-Benzyoxycarbonylamino acetic acid (46.2 mg, 0.241 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (46.2 mg, 0.241 mmol), I-hydroxybenzotriazole (15.4 mg, 0.100 mmol), carry out stirring for 20 hours.In reaction solution, add distilled water, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 57 (33.2 mg, 0.058 mmol, 29%) with colourless armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.91-2.07?(8H,?m),?2.33?(3H,?s),?2.75?(1H,?s),?3.80?(3H,?s),?3.98-3.99?(2H,?m),?4.89-4.94?(1H,?m),?5.14?(2H,?s),?5.33-5.35?(1H,?m),?6.36?(1H,?s),?6.82-6.86?(2H,?m),?7.08-7.10?(4H,?m),?7.17-7.21?(2H,?m),?7.29-7.38?(5H,?m).
ESI-MS:?m/z=?552?(M-OH)
+。
(intermediate 58)
According to following order, synthesize 2-(Benzyoxycarbonylamino)-3 Methylbutanoic acid (S)-4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl ester as intermediate 58 according to the method same with intermediate 57.
[changing 92]
1H-NMR?(400?MHz,?CDCl
3)?δ:?0.92?(3H,?d,?J=6.4Hz),?0.99?(3H,?d,?J=6.4?Hz),?1.89-2.10?(8H,?m),?2.16-2.24?(1H,?m),?2.34?(3H,?s),?2.63?(1H,?s),?3.81?(3H,?s),?4.30-4.33?(1H,?m),?4.88-4.95?(1H,?m),?5.12?(2H,?s),?5.28-5.30?(1H,?m),?6.36?(1H,?s),?6.78-6.82?(2H,?m),?7.09-7.10?(4H,?m),?7.18-7.24?(2H,?m),?7.29-7.38?(5H,?m).
ESI-MS:?m/z=?594?(M-OH)
+。
(intermediate 59)
According to 2-(Benzyoxycarbonylamino)-3 Methylbutanoic acid (S)-4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) the cyclohexyl oxygen base of following order synthesis as intermediate 59) methyl esters.
[changing 93]
At room temperature, in 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-cis-1,4-glycol (compound 3) (199 mg, 0.506 mmol) methylene dichloride (3.00 mL) solution add molecular sieve 4A (300 mg) and diisopropylethylamine (0.210 mL, 1.21 mmol), be cooled to-50 DEG C.Then, add 2-benzyloxycarbonyl amino-3 Methylbutanoic acid (S)-iodo-methyl ester (0.187 mL, 1.26 mmol), silver trifluoromethanesulfonate (232 mg, 0.904 mmol) at such a temperature, stir after 2 hours, stir 14 hours at-30 DEG C.In reaction solution, add saturated sodium bicarbonate water, use diatomite filtration.Filtrate is used salt water washing, by organic over anhydrous dried over sodium sulfate, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 59 (123 mg, 0.192 mmol, 64%) with colourless armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?0.92?(3H,?d,?J=6.4?Hz),?1.01?(3H,?d,?J=6.4?Hz),?1.88-1.99?(6H,?m),?2.02-2.09?(2H,?m),?2.20-2.26?(1H,?m),?2.34?(3H,?s),?2.50?(1H,?s),?3.66-3.72?(1H,?m),?3.81?(3H,?s),?4.32-4.36?(1H,?m),?5.12?(2H,?s),?5.38?(1H,?d,?J=6.4?Hz),?5.50?(1H,?d,?J=6.4?Hz),?6.37?(1H,?s),?6.83-6.87?(2H,?m),?7.08-7.11?(4H,?m),?7.18-7.24?(2H,?m),?7.29-7.38?(5H,?m).
ESI-MS:?m/z=?624?(M-OH)
+。
(intermediate 60)
According to 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-cis-cyclohexyl di(2-ethylhexyl)phosphate benzyl ester of following order synthesis as intermediate 60.
[changing 94]
Under ice-cooled stirring, in 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-cis-1,4-glycol (compound 3) (200 mg, 0.528 mmol) tetrahydrofuran (THF) (2.6 mL) solution in add 55% sodium hydride (55.3 mg successively, 1.27 mmol) and burnt phosphonic acids tetrabenzyl ester (370 mg, 0.687 mmol), at room temperature stir 15 hours.Reaction solution is ice-cooled, add water, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 60 (251 mg, 0.393 mmol, 74%) with the form of water white transparency oily compound.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.87-2.11?(8H,?m),?2.33?(3H,?s),?3.79?(3H,?s),?4.42-4.51?(1H,?m),?5.00-5.12?(4H,?m),?6.34?(1H,?s),?6.81-6.87?(2H,?m),?7.09?(4H,?s),?7.16-7.23?(2H,?m),?7.29-7.37?(10H,?m).
ESI-MS:?m/z=?639?(M+H)
+。
(compound 4)
According to 4-hydroxyl-4-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl) hexanaphthene-1-ketone of following order synthesis as compound 4.
[changing 95]
At 8-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 18) (14.6 g, 34.7 mmol) tetrahydrofuran (THF) (69.4 mL) solution add 6 M hydrochloric acid (138.9 mL), at room temperature stir 15 hours.Reaction solution is ice-cooled, at 0 DEG C, drip 50% aqueous sodium hydroxide solution, until in alkalescence, be then extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates by recrystallization (n-hexane/ethyl acetate, 70 DEG C) purifying, obtain compound 4 (10.5 g, 27.9 mmol, 80%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.33-2.43?(9H,?m),?2.87-2.95?(3H,?m),?3.82?(3H,?s),?6.39?(1H,?s),?6.86?(2H,?d,?J=8.8?Hz),?7.10?(4H,?s),?7.22?(2H,?d,?J=8.8?Hz).
IR?(KBr,?cm
-1):?3321,?2929,?1712,?1518,?1463,?1299,?1249,?1179,?1114,?1027,?961,?821.
ESI-MS:?m/z=?377?(M+H)
+。
(intermediate 62)
According to 4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-(6-picoline-3-the base)-1H-pyrazole-3-yl)-hexanaphthene-1-ketone of following order synthesis as compound 62.
[changing 96]
At 8-(1-(4-p-methoxy-phenyl)-5-(6-picoline-3-base)-1H-pyrazole-3-yl)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 19) (128.8 mg, 0.30 mmol) tetrahydrofuran (THF) (0.6 mL) solution in add 6 M hydrochloric acid (1.2 mL), at room temperature stir 3 hours.Reaction solution is ice-cooled, at 0 DEG C, drip 50% aqueous sodium hydroxide solution, until in alkalescence, be then extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 62 (109.5 mg, 0.29 mmol, 96%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.34-2.44?(6H,?m),?2.55?(3H,?s),?2.87-2.95?(2H,?m),3.18?(1H,?s),?3.82?(3H,?s),?6.49?(1H,?s),?6.87?(2H,?d,?J=8.8?Hz),?7.08?(1H,?d,?J=8.1?Hz),?7.19?(2H,?d,?J=8.8?Hz),?7.35?(1H,?dd,?J=2.2,?8.1?Hz),?8.40?(1H,?d,?J=2.2?Hz).
ESI-MS:?m/z=?378?(M+H)
+。
(intermediate 63)
According to 4-(1,5-two (4-p-methoxy-phenyl)-1H-pyrazole-3-yl)-4-hydroxy-cyclohexan alkane-1-ketone of following order synthesis as compound 63.
[changing 97]
At 0 DEG C, at 8-(1, two (4-the p-methoxy-phenyl)-1H-pyrazole-3-yl of 5-)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 20) (658 mg, 1.50 mmol) tetrahydrofuran (THF) (3.75 mL) solution in add 6 M hydrochloric acid (7.5 mL), at room temperature stir 5 hours.Be injected into by reaction solution in 10% ice-cooled aqueous sodium hydroxide solution, neutralization, adds saturated sodium bicarbonate water, makes alkalescence, be extracted with ethyl acetate.By organic over anhydrous dried over mgso, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 63 (523 mg, 1.33 mmol, 89%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.30-2.45?(6H,?m),?2.86-2.96?(2H,?m),?2.99?(1H,?s),?3.80?(3H,?s),?3.82?(3H,?s),?6.36?(1H,?s),?6.82?(2H,?d,?J=8.8?Hz),?6.87?(2H,?d,?J=8.8?Hz),?7.13?(2H,?d,?J=8.8?Hz),?7.21?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?393?(M+H)
+。
(intermediate 64)
According to 4-(5-(4-chloro-phenyl-)-1-(4-p-methoxy-phenyl)-1H-the pyrazole-3-yl)-4-hydroxy-cyclohexan alkane-1-ketone of following order synthesis as compound 64.
[changing 98]
At 8-(5-(4-chloro-phenyl-)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 21) (756 mg, 1.71 mmol) tetrahydrofuran (THF) (4.3 mL) solution in add 6 M hydrochloric acid (8.6 mL), at room temperature stir 15 hours.Reaction solution is ice-cooled, at 0 DEG C, drip 50% aqueous sodium hydroxide solution, until in alkalescence, be then extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 64 (619 mg, 1.56 mmol, 91%) with armorphous form.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.31-2.45?(6H,?m),?2.85-2.98?(3H,?m),?3.82?(3H,?s),?6.43?(1H,?s),?6.86-6.90?(2H,?m),?7.14?(2H,?d,?J=8.8?Hz),?7.19?(2H,?d,?J=8.8?Hz),?7.26-7.29?(2H,?m).
ESI-MS:?m/z=?397?(M+H)
+。
(intermediate 65)
According to 4-hydroxyl-4-(1-(4-the chloro-phenyl-)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-1-ketone of following order synthesis as compound 65.
[changing 99]
At 8-(1-(4-chloro-phenyl-)-5-p-methylphenyl-1H-pyrazole-3-yl)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 22) (931 mg, 2.19 mmol) tetrahydrofuran (THF) (5.5 mL) solution in add 6 M hydrochloric acid (11 mL), at room temperature stir 15 hours.Reaction solution is injected in saturated sodium bicarbonate aqueous solution, makes alkalescence, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 65 (513 mg, 1.35 mmol, 61%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.32-2.36?(4H,?m),?2.36?(3H,?s),?2.38-2.44?(2H,?m),?2.87-2.95?(2H,?m),?2.90?(1H,?s),?6.41?(1H,?s),?7.10?(2H,?d,?J=8.0?Hz),?7.14?(2H,?d,?J=8.0?Hz),?7.23?(2H,?d,?J=8.8?Hz),?7.31?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?381?(M+H)
+。
According to the method same with the synthesis of above-mentioned intermediate, synthesize following compound.
[table 13-1]
[table 13-2]
[table 13-3]
(intermediate 81)
According to acetic acid 4-(4-chloro-1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-the pyrazole-3-yl)-c-4-hydroxy-cyclohexan alkane-r-1-base ester of following order synthesis as compound 81.
[changing 100]
At acetic acid c-4-hydroxyl-4-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester (compound 12) (140 mg, 0.333 mmol) acetonitrile (1.66 mL) solution in add N-chlorosuccinimide (49 mg, 0.366 mmol), stir 15 hours at 80 DEG C, be cooled to room temperature.In reaction solution, add salt solution, be extracted with ethyl acetate.By organic over anhydrous dried over mgso, concentrating under reduced pressure, by resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtains intermediate 81 (67 mg, 0.147 mmol, 44%) as a white solid.
1H-NMR?(400MHz,?CDCl
3)?δ:?1.92-2.04?(6H,?m),?2.28-2.36?(8H,?m),?3.10?(1H,?s),?3.79?(3H,?s),?4.85-4.88?(1H,?m),?6.80-6.82?(2H,?m),?7.11-7.16?(6H,?m)。
(intermediate 82)
According to following order synthesis 4-(two (4-p-methoxy-phenyl) oxazole-2-base)-4-hydroxycyclohexan-1-ketone of 4,5-as compound 82.
[changing 101]
At 0 DEG C, at 8-(4, two (the 4-p-methoxy-phenyl) oxazole-2-base)-1 of 5-, add 6 M hydrochloric acid (9.0 mL) in tetrahydrofuran (THF) (4.5 mL) solution of 4-dioxo spiro [4.5] decane-8-alcohol (intermediate 52) (781 mg, 1.78 mmol), at room temperature stir 2 hours.Reaction solution is cooled to 0 DEG C, adds 10% aqueous sodium hydroxide solution and saturated sodium bicarbonate water, make alkalescence, be extracted with ethyl acetate.Use anhydrous magnesium sulfate drying organic layer, concentrating under reduced pressure.By resistates by recrystallization (ethyl acetate/normal hexane) purifying, obtain intermediate 82 (445 mg, 1.13 mmol, 63%) with the form of faint yellow solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?2.32-2.54?(6H,?m),?2.81-2.92?(2H,?m),?3.17?(1H,?m),?3.84?(6H,?s),?6.90?(2H,?d,?J=8.8?Hz),?6.91?(2H,?d,?J=8.8?Hz),?7.49?(2H,?d,?J=8.8Hz),?7.56?(2H,?d,?J=8.8?Hz).
ESI-MS:?m/z=?394?(M+H)
+。
(intermediate 83)
According to 4-hydroxyl-4-(4-(4-the p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl) hexanaphthene-1-ketone of following order synthesis as compound 83.
[changing 102]
At 0 DEG C, at 8-(4-(4-p-methoxy-phenyl)-5-p-methylphenyl thiazol-2-yl)-1,4-dioxo spiro [4.5] decane-8-alcohol (intermediate 56) (469 mg, 1.07 mmol) tetrahydrofuran (THF) (5.4 mL) solution in add 6 M hydrochloric acid (5.4 mL), at room temperature stir 14 hours.Reaction solution is injected in saturated sodium bicarbonate aqueous solution, makes alkalescence, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 83 (352 mg, 0.895 mmol, 83%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)δ:?2.33-2.51?(6H,?m),?2.37?(3H,?s),?2.86-2.95?(2H,?m),?3.50?(1H,?s),?3.81?(3H,?s),?6.81-6.84?(2H,?m),?7.14?(2H,?d,?J=8.0?Hz),?7.24?(2H,?d,?J=8.0?Hz),?7.44-7.48?(2H,?m).
ESI-MS:?m/z=?394?(M+H)
+。
(intermediate 84)
According to acetic acid c-4-hydroxyl-1-(1-(4-the p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-r-1-base ester of following order synthesis as compound 84.
[changing 103]
In oxalic acid 1-(1-(4-p-methoxy-phenyl)-5-p-methylphenyl-1H-pyrazole-3-yl)-hexanaphthene-cis-1,4-bis-base ester (intermediate 38) (297 mg, 0.642 mmol) methyl alcohol (4.3 mL) solution add salt of wormwood (89.0 mg, 0.642 mmol), at room temperature stir 4 hours.In reaction solution, add water, stopped reaction, be extracted with ethyl acetate.By organic layer washed with brine, with anhydrous sodium sulfate drying, concentrating under reduced pressure.By resistates flash column chromatography (silica gel, n-hexane/ethyl acetate) purifying, obtain intermediate 84 (213 mg, 0.507 mmol, 79%) as a white solid.
1H-NMR?(400?MHz,?CDCl
3)?δ:?1.49?(1H,?d,?J=4.4?Hz),?1.65-1.74?(2H,?m),?1.90-1.98?(4H,?m),?2.10?(3H,?s),?2.32?(3H,?s),?2.71-2.78?(2H,?m),?3.74-3.81?(4H,?m),?6.37?(1H,?s),?6.83?(2H,?d,?J=9.2?Hz),?7.08?(4H,?s),?7.20?(2H,?d,?J=9.2?Hz).
ESI-MS:?m/z=?421?(M+H)
+。
Industrial applicability
Cyclohexane derivant of the present invention or the acceptable salt of its pharmacology can be used for therapeutical agent or the preventive of medicine, particularly retention of urine obstacle using them as effective constituent.
Claims (5)
1. the therapeutical agent of retention of urine obstacle or preventive, it contains the cyclohexane derivant shown in general formula (I), the acceptable salt of its pharmacology as effective constituent:
In formula, A is the substituting group shown in general formula (IIa),
R
1and R
2respective independence is the alkyl of carbonatoms 1-4 or the alkoxyl group of carbonatoms 1-4,
R
3for hydrogen atom, R
4for hydroxyl,
R
5and R
6respective independence is hydrogen atom or hydroxyl,
R
7and R
8for hydrogen atom,
Z is methyne.
2. the therapeutical agent of claim 1 or preventive, wherein, R
1for methyl, R
2methoxyl group, R
5for hydroxyl, R
6for hydrogen atom.
3. the cyclohexane derivant shown in general formula (I), the application of the acceptable salt of its pharmacology in the medicine of the treatment use or prevention of preparing retention of urine obstacle:
In formula, A is the substituting group shown in general formula (IIa),
R
1and R
2respective independence is the alkyl of carbonatoms 1-4 or the alkoxyl group of carbonatoms 1-4,
R
3for hydrogen atom, R
4for hydroxyl,
R
5and R
6respective independence is hydrogen atom or hydroxyl,
R
7and R
8for hydrogen atom,
Z is methyne.
4. the purposes of claim 3, wherein, R
1for methyl, R
2methoxyl group, R
5for hydroxyl, R
6for hydrogen atom.
5. the purposes of claim 3 or 4, wherein, above-mentioned retention of urine obstacle is frequent micturition, the urinary incontinence or urgency.
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PCT/JP2011/058220 WO2011125838A1 (en) | 2010-03-31 | 2011-03-31 | Therapeutic agent or preventive agent for urine collection disorder |
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EP2562160B1 (en) | 2014-09-10 |
CN102812008A (en) | 2012-12-05 |
WO2011125838A1 (en) | 2011-10-13 |
AU2011237074B2 (en) | 2014-10-02 |
BR112012022944B1 (en) | 2021-08-31 |
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US8642625B2 (en) | 2014-02-04 |
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